Submissions for variant NM_000071.3(CBS):c.473C>T (p.Ala158Val)

gnomAD frequency: 0.00001  dbSNP: rs1376851289

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002024992	SCV002272569	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-08-24	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 158 of the CBS protein (p.Ala158Val). This missense change has been observed in individual(s) with clinical features of homocystinuria due to cystathionine beta-synthase deficiency (PMID: 9590298, 22267502; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 22267502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function. ClinVar contains an entry for this variant (Variation ID: 1481680).
GeneDx	RCV004770339	SCV005376905	likely pathogenic	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on protein function (PMID: 22267502, 9590298); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22267502, 9590298, 26667307)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238137	SCV005886076	likely pathogenic	Homocystinuria	2025-02-17	criteria provided, single submitter	clinical testing	Variant summary: CBS c.473C>T (p.Ala158Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 173422 control chromosomes. c.473C>T has been reported in the literature in individuals affected with Homocystinuria and segregated with disease in at least one family (Gong_2015, Shan_1998, Labcorp (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Mayfield_2012). The following publications have been ascertained in the context of this evaluation (PMID: 26667307, 22267502, 9590298). ClinVar contains an entry for this variant (Variation ID: 1481680). Based on the evidence outlined above, the variant was classified as likely pathogenic.