Submissions for variant NM_000071.3(CBS):c.502G>A (p.Val168Met)

dbSNP: rs121964970

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179250	SCV000231470	uncertain significance	not provided	2017-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000179250	SCV000249683	likely pathogenic	not provided	2021-05-19	criteria provided, single submitter	clinical testing	Has been reported in individuals with B6-responsive homocystinuria (Kruger et al., 1995; Shan et al., 1998), as well as an individual with spontaneous coronary artery dissection (SCAD) (Kaadan et al., 2018).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies in yeast have demonstrated that V168M results in a non-functional allele with impaired CBS function (Shan et al., 1998; Mayfield et al., 2012).; Reported in ClinVar (ClinVar Variant ID# 127; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10338090, 10531322, 31301157, 8528202, 22267502, 29650765, 9590298, 11230183, 20066033)
Ambry Genetics	RCV002310622	SCV000317362	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-08-22	criteria provided, single submitter	clinical testing	The p.V168M pathogenic mutation (also known as c.502G>A), located in coding exon 4 of the CBS gene, results from a G to A substitution at nucleotide position 502. The valine at codon 168 is replaced by methionine, an amino acid with highly similar properties. This variant was first reported as detected in cell lines from an individual with inferred clinical phenotype of homozygous CBS enzyme deficiency; however, clinical details were not provided, this variant was detected in the heterozygous state, and the potential of sample and clinical information misclassification was suggested (Kruger WD et al. Hum Mol Genet. 1995;4:1155-61). This variant was also detected in an individual from a coronary artery dissection cohort who had a second CBS variant (phase unknown), no typical disease features, and normal serum homocysteine levels (Kaadan MI et al. Circ Genom Precis Med. 2018;11:e001933). Studies have indicated that this variant results in reduced protein and enzyme activity in yeast assays (Kabil O et al. J Biol Chem. 1999;274:31256-60; Shan X et al. Hum Mol Genet. 2001;10:635-43; Singh LR et al. PLoS Genet. 2010;6:e1000807; Mayfield JA et al. Genetics. 2012;190:1309-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002227959	SCV000543513	likely pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 168 of the CBS protein (p.Val168Met). 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 missense change has been observed in individual(s) with homocystinuria due to cystathionine beta-synthase deficiency (PMID: 8528202, 33985475; Invitae). 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: 127). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 8528202, 10531322, 20066033, 22267502). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV000458159	SCV001298058	uncertain significance	Classic homocystinuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265542	SCV002547805	likely pathogenic	Homocystinuria	2022-05-21	criteria provided, single submitter	clinical testing	Variant summary: CBS c.502G>A (p.Val168Met) results in a conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 186900 control chromosomes. c.502G>A has been reported in the literature as a non-informative genotype in CBS cell lines, in presumed compound heterozygosity in an individual with Spontaneous Coronary Artery Dissection and as a confirmed compound heterozygous genotype in an individual presenting with Recurrent dislocation of binocular crystal lenses and cystathionine beta synthase deficiency (example, Kruger_1995, Kaadan_2018, Hua_2021). At least two publications report experimental evidence evaluating an impact on protein function (example, Kabil_1999, Singh_2010). The most pronounced variant effect results in <10% of normal cystathionine beta synthase activity in vitro. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely pathogenic, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000458159	SCV004171931	likely pathogenic	Classic homocystinuria		criteria provided, single submitter	clinical testing	The missense c.502G>A (p.Val168Met) variant in CBS gene has been reported in individuals with Homocystinuria cystathionine beta synthase (CBS) deficiency (Hua N et al. 2021; Kaadan MI et al. 2018). Experimental studies have shown that this missense change affects CBS function (Mayfield JA et al. 2012). The p.Val168Met variant has allele frequency 0.001% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain significance / Pathogenic / Likely Pathogenic (multiple submiters). The amino acid change p.Val168Met in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 168 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000458159	SCV004213878	likely pathogenic	Classic homocystinuria	2023-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004540986	SCV005040796	likely pathogenic	Familial hypercholesterolemia	2024-03-09	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251288 control chromosomes (gnomAD). c.502G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Taylor_2010, Rall_2014, Sanchez-Hernandez_2016, Wald-2016). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in an impaired LDL binding capacity of WT. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000150	SCV000020293	pathogenic	Homocystinuria, pyridoxine-responsive	2003-12-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000458159	SCV002083807	uncertain significance	Classic homocystinuria	2020-03-05	no assertion criteria provided	clinical testing