1-173904011-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_ModeratePM5PP3PP4PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210762/MONDO:0013144/084
Frequency
Consequence
NM_000488.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINC1 | NM_000488.4 | c.1273C>T | p.Arg425Cys | missense_variant | Exon 7 of 7 | ENST00000367698.4 | NP_000479.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251344Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74458
ClinVar
Submissions by phenotype
Hereditary antithrombin deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 30, 1988 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 24, 2019 | This sequence change replaces arginine with cysteine at codon 425 of the SERPINC1 protein (p.Arg425Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121909554, ExAC 0.01%). This variant has been observed in several individuals with antithrombin deficiency and segregates with disease in at least one family (PMID: 22481271, 27098529, 3179448, 3179448, 4049307). This variant is also known as R393C, Arg393Cys, and Antithrombin III Northwick Park in the literature. ClinVar contains an entry for this variant (Variation ID: 18016). This variant has been reported to affect SERPINC1 protein function (PMID: 22481271). This variant disrupts the p.Arg425 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 22481271, 28317092), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | Clingen Thrombosis Variant Curation Expert Panel, ClinGen | Aug 16, 2024 | The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID: 27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at