Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001232043 | SCV001404587 | pathogenic | Thrombophilia due to protein S deficiency, autosomal recessive | 2021-08-23 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs387906674, ExAC 0.05%). This sequence change replaces arginine with cysteine at codon 355 of the PROS1 protein (p.Arg355Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been observed in individual(s) with protein S deficiency (PMID: 29748776, 21764702, 27667277, 21172841, 21486865, 27748013). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg314Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 29846). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg355 amino acid residue in PROS1. Other variant(s) that disrupt this residue have been observed in individuals with PROS1-related conditions (PMID: 15238143), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
3billion | RCV000022724 | SCV002318475 | likely pathogenic | Thrombophilia due to protein S deficiency, autosomal dominant | 2022-03-22 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PROS1 related disorder (ClinVar ID: VCV000029846, PMID:21172841). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000956390, PMID:15238143). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.826>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
OMIM | RCV000022724 | SCV000044013 | pathogenic | Thrombophilia due to protein S deficiency, autosomal dominant | 2010-12-14 | no assertion criteria provided | literature only |