Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.0.0

Description : This version specified for the following gene: ENG

Version : 1.0.0

Hereditary Hemorrhagic Telangiectasia VCEP

Released

3/5/2024

15:43:11

Rules for ENG

Gene: ENG (HGNC:3349) HGNC Name: endoglin Transcripts: NM_001114753.3 Disease: telangiectasia, hereditary hemorrhagic, type 1 (MONDO:0008535) Mode of Inheritance: Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Use ENG PVS1 Decision Tree (see attachments) Modification Type: Gene-specific,Strength Strong Use ENG PVS1 Decision Tree (see attachments) Modification Type: Gene-specific,Strength Moderate Use ENG PVS1 Decision Tree (see attachments) Modification Type: Gene-specific,Strength Supporting Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Modification Type: No change Moderate Supporting Instructions: No modification. Use as applicable. Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Strong De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Modification Type: Clarification,Disease-specific Moderate Supporting Instructions: Due to the highly variable phenotype and age-related penetrance in HHT, to be considered unaffected the parents should be over age 40 and have no history of epistaxis or telangiectases (see additional information in HHT phenotype document attached). Note: low-level mosaicism has been observed in parents of individuals with HHT (PMID: 29736967, PMID: 21651515, PMID: 21378382, PMID: 21415079). Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong mRNA splicing assays can be used as strong functional evidence. Note: level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact. Modification Type: Disease-specific,Strength Moderate See PS3_Supporting and Instructions below. Modification Type: Disease-specific,Strength Supporting Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2 Note: Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn. Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI) Subcellular protein localization Morphology: Morphology & actin cytoskeleton, tubulogenesis Somatic variant 2^nd hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786). Modification Type: Disease-specific,Strength Instructions: HHT assays can be used as supporting evidence and bumped up to moderate/strong criteria if multiple different functional assays are concordant. Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong 4+ probands with phenotype consistent with HHT. Modification Type: Disease-specific Moderate 2-3 probands with phenotype consistent with HHT. Modification Type: Disease-specific Supporting 1 proband with phenotype consistent with HHT. Modification Type: Disease-specific Instructions: Variant must also meet PM2_Supporting. See HHT phenotype document in attachments for phenotype requirements. Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Apply if variant is located in a critical residue: ENG: BMP9 binding sites: S278, F282 (PMIDs 28564608, 25312062) Cysteine residues either previously reported to be likely pathogenic or pathogenic: C207, C363, C382, C412, C549 Or cysteine residues known to be important for ENG function: C350 (C350-C382 disulfide in ZP-N domain of ENG is required for secretion of its ZP module) C394 (makes a disulfide bond with C412 which is reported to be a mutated residue) C516 (involved in forming intermolecular disulfides that hold ENG homodimer together) C582 (involved in forming intermolecular disulfides that hold ENG homodimer together) Modification Type: Gene-specific Supporting Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting <6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations. Modification Type: Disease-specific,Strength Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: HHT is autosomal dominant disorder.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Modification Type: None Supporting Instructions: No modification. Use as applicable. Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong ≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules. Modification Type: Disease-specific,Strength Moderate A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules. Modification Type: Disease-specific,Strength Supporting Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT.
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong 5+ meioses (1/32 likelihood) Modification Type: Disease-specific,Strength Moderate 4 meioses (1/16 likelihood) Modification Type: Disease-specific,Strength Supporting 3 meioses (1/8 likelihood) Modification Type: Disease-specific,Strength Instructions: See HHT phenotype document in attachments for assignment of affected/unaffected status for purpose of inclusion in cosegregation study. Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply to ENG (Z-score= 0.93).
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2. For synonymous and intronic variants: SpliceAI score ≥0.2. Modification Type: Disease-specific Instructions: SpliceAI (PMID: 30661751): https://spliceailookup.broadinstitute.org/ REVEL (PMID: 27666373) Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both ENG and ACVRL1 with any other identified variants ruled out. Modification Type: Disease-specific,Strength Supporting Instructions: PP4_Moderate cannot be applied to variants that meet BS1_Supporting/BS1/BA1 criteria. See HHT phenotype document in attachments for information regarding Curacao phenotype requirements. Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong >0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, or if variant meets BS1_Supporting and has ≥2 homozygotes. Modification Type: Disease-specific,Strength Moderate Supporting >0.08% to 0.2% (based on gnomAD Popmax FAF). Modification Type: Disease-specific,Strength Instructions: HHT is not known to be enriched in bottlenecked populations (e.g. Ashkenazi Jewish); therefore, Popmax FAF can be calculated and applied for bottlenecked populations for BS1 and BS1_Supporting criteria. Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Full penetrance at an early age is not observed in HHT.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting mRNA splicing assays Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI) Subcellular protein localization Morphology: Morphology & actin cytoskeleton, tubulogenesis Modification Type: Disease-specific,Strength Instructions: Normal protein expression cannot be used as benign evidence because protein function can still be altered (e.g. pathogenic dominant negative variants have been reported in HHT with no effect on protein expression). Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Lack of segregation in affected members of a family. Modification Type: Clarification,Disease-specific Moderate Supporting Instructions: See HHT phenotype document in attachments for assignment of affected/unaffected status for purpose of inclusion in cosegregation study. Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Missense variants commonly seen in HHT genes
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules. Modification Type: Disease-specific Instructions: Variants must be confirmed in trans. Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1. For synonymous and intronic variants: SpliceAI score ≤0.1. Modification Type: Disease-specific Instructions: SpliceAI (PMID: 30661751): https://spliceailookup.broadinstitute.org/ REVEL (PMID: 27666373) Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in ACVRL1. Modification Type: Disease-specific Instructions: Do not apply this for other vascular genes as the phenotype is different (e.g. RASA1, SMAD4). Co-occurrences of a pathogenic variant with a possibly mild hypomorphic variant (e.g. ENG c.-9G>A) has been seen. Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence. Modification Type: Disease-specific Instructions: For synonymous and intronic variants: SpliceAI score ≤0.1. Note: If no causative variant is found in ENG or ACVRL1, and the patient's clinical presentation and/or family history is highly suspicious for HHT, be careful to not dismiss intronic variants or synonymous variants in the last nucleotide of the exon based on computational predictions. Example 1: ENG c.1852+42C>T is not predicted to alter splicing (SpliceAI: 0.00) and several alleles are reported in gnomAD (0.05% (15 alleles, Latino), 0.01% overall (24/217994 alleles)), but it does not meet the cutoff for applying BS1_Supporting (>0.08%). This variant does not alter splicing but rather a Sp1 binding site, and was confirmed to have a pathogenic role showing it significantly reduces ENG transcription by affecting this novel Sp1 binding-site (PMID: 29305977). Example 2: ENG c.219G>A; p.Thr73= is not predicted to significantly alter splicing (SpliceAI: 0.02) and the nucleotide is weakly conserved. However, this variant was later shown to cause exon skipping (PMID: 17384219, ARUP Laboratories). **IMPORTANT: SpliceAI does not predict splicing effects for some deep intronic ACVRL1 intron 9 CT rich hotspot variants (PMID: 30244195). Therefore, variants that create a new 'AG' cryptic splice site in this region, should not be ruled out based on SpliceAI prediction alone.** Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong)

1 Very Strong (PVS1) AND ≥ 2 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1) AND 1 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate) AND 1 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

1 Very Strong (PVS1) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

Likely Pathogenic

1 Very Strong (PVS1) AND 1 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

≥ 3 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

1 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1) AND 1 Supporting (PM2_Supporting)

Benign

≥ 2 Strong (BS1, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS4) AND 1 Supporting (BS1_Supporting, BS3_Supporting, BP2, BP4, BP5, BP7)

≥ 2 Supporting (BS1_Supporting, BS3_Supporting, BP2, BP4, BP5, BP7)

1 Strong (BS1)

Files & Images

HHT Phenotype: Requirements for applying evidence codes.

ENG PVS1 Decision Tree:

HHT Functional Assays:

References

1. McDonald J Wooderchak-Donahue WL et al. Tissue-specific mosaicism in hereditary hemorrhagic telangiectasia: Implications for genetic testing in families. Am J Med Genet A (2018) 176 (7) p. 1618-1621. 10.1002/ajmg.a.38695 29736967

2. Eyries M Coulet F et al. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clin Genet (2012) 82 (2) p. 173-9. 10.1111/j.1399-0004.2011.01727.x 21651515

3. Best DH Vaughn C et al. Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. J Med Genet (2011) 48 (5) p. 358-60. 10.1136/jmg.2010.088286 21378382

4. Lee NP Matevski D et al. Identification of clinically relevant mosaicism in type I hereditary haemorrhagic telangiectasia. J Med Genet (2011) 48 (5) p. 353-7. 10.1136/jmg.2010.088112 21415079

5. Jaganathan K Kyriazopoulou Panagiotopoulou S et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell (2019) 176 (3) p. 535-548.e24. 10.1016/j.cell.2018.12.015 30661751

6. Ioannidis NM Rothstein JH et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet (2016) 99 (4) p. 877-885. 10.1016/j.ajhg.2016.08.016 27666373

7. Plumitallo S Ruiz-Llorente L et al. Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site. Gene (2018) 647 p. 85-92. 10.1016/j.gene.2018.01.007 29305977

8. Gedge F McDonald J et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn (2007) 9 (2) p. 258-65. 10.2353/jmoldx.2007.060117 17384219

9. Wooderchak-Donahue WL McDonald J et al. Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. J Med Genet (2018) 55 (12) p. 824-830. 10.1136/jmedgenet-2018-105561 30244195

10. Snellings DA Gallione CJ et al. Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. Am J Hum Genet (2019) 105 (5) p. 894-906. 10.1016/j.ajhg.2019.09.010 31630786

11. Faughnan ME Mager JJ et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med (2020) 173 (12) p. 989-1001. 10.7326/M20-1443 32894695

12. Porteous ME Burn J et al. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet (1992) 29 (8) p. 527-30. 10.1136/jmg.29.8.527 1518020

13. Berg J Porteous M et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet (2003) 40 (8) p. 585-90. 10.1136/jmg.40.8.585 12920067

14. Arthur H Geisthoff U et al. Executive summary of the 11th HHT international scientific conference. Angiogenesis (2015) 18 (4) p. 511-24. 10.1007/s10456-015-9482-5 26391603

15. Anderson E Sharma L et al. Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia. Thorax (2022) 77 (6) p. 628-630. 10.1136/thoraxjnl-2021-218332 35165143

16. Revuz S Decullier E et al. Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability. PLoS One (2017) 12 (10) p. e0184227. 10.1371/journal.pone.0184227 28981519

17. Shovlin CL Guttmacher AE et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet (2000) 91 (1) p. 66-7. 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p 10751092