Submissions for variant NM_000071.3(CBS):c.1007G>C (p.Arg336Pro)

dbSNP: rs760417941

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003154014	SCV001557199	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2024-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 336 of the CBS protein (p.Arg336Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CBS deficiency (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1052953). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10408774, 12815602, 16205833, 16429402, 21517828, 26464485). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002420789	SCV002725410	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-08-04	criteria provided, single submitter	clinical testing	The p.R336P variant (also known as c.1007G>C), located in coding exon 9 of the CBS gene, results from a G to C substitution at nucleotide position 1007. The arginine at codon 336 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported as compound heterozygous with a known pathogenic mutation in CBS in an individual with homocystinuria (Ambry internal data). Another alteration at the same codon, p.R336H (c.1007G>A), has been detected as homozygous in two family members with homocystinuria (Coudé M et al. J Inherit Metab Dis, 1998 Dec;21:823-8), and showed an impact on enzyme activity in functional studies (Urreizti R et al. Hum Mutat, 2006 Feb;27:211; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Mendes MI et al. Hum Mol Genet, 2015 Dec;24:7339-48). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Natera, Inc.	RCV001361230	SCV002083782	uncertain significance	Classic homocystinuria	2020-04-24	no assertion criteria provided	clinical testing