Submissions for variant NM_000071.3(CBS):c.992C>T (p.Ala331Val)

dbSNP: rs777919630

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173977	SCV000225193	uncertain significance	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516607	SCV003256154	likely pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 331 of the CBS protein (p.Ala331Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of homocystinuria (PMID: 33057012). ClinVar contains an entry for this variant (Variation ID: 193793). 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, 22267502). This variant disrupts the p.Ala331 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9156316; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Baylor Genetics	RCV003462276	SCV004213902	likely pathogenic	Classic homocystinuria	2024-03-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004601121	SCV005098231	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-05-31	criteria provided, single submitter	clinical testing	The p.A331V variant (also known as c.992C>T), located in coding exon 9 of the CBS gene, results from a C to T substitution at nucleotide position 992. The alanine at codon 331 is replaced by valine, an amino acid with similar properties. This alteration has been reported as homozygous in two siblings with homocystinuria (Kaur R et al. Sci Rep, 2020 Oct;10:17299). Based on internal structural analysis, this alteration is deleterious, being moderately destabilizing to the local structure (Kruger WD et al. Hum Mutat. 2003 Dec;22(6):434-41). Additionally, in vitro assays showed this alteration has residual protein function (Kruger WD et al. Hum Mol Genet, 1995 Jul;4:1155-61; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). This amino acid position is poorly 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003462276	SCV005849398	likely pathogenic	Classic homocystinuria		criteria provided, single submitter	clinical testing	The observed missense variant c.992C>T(p.Ala331Val) in CBS gene has been reported previously in homozygous state in individuals affected with Thrombosis, hyperhomocysteinemic (Kaur R et. al., 2020). Experimental studies have shown that this missense change affects CBS function (Mayfield et al., 2012). This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid Ala at position 331 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala331Val in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT -Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. This variant has been partially explaining the phenotype. For these reasons, the variant has been classified as Likely Pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252181	SCV001427931	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing