Submissions for variant NM_000071.3(CBS):c.397G>A (p.Asp133Asn)

gnomAD frequency: 0.00019  dbSNP: rs539326697

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198043	SCV000249680	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000243532	SCV000318099	uncertain significance	Cardiovascular phenotype	2012-12-04	criteria provided, single submitter	clinical testing	Co-segregation data for this variant is currently unavailable. This variant has not been detected in conjunction with a pathogenic mutation to date. Allele frequency data in population-based cohorts is not currently available. This amino acid position is poorly conserved in available vertebrate species.This alteration is predicted to be benign with a score of 0.006 (sensitivity: 0.97; specificity: 0.43)This alteration is predicted to be tolerated with a score of 0.110 (conservation: 2.74)
Genome-Nilou Lab	RCV001271170	SCV001781419	uncertain significance	Classic homocystinuria	2021-07-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277460	SCV002566494	uncertain significance	Connective tissue disorder	2018-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517162	SCV003253633	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-07-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 133 of the CBS protein (p.Asp133Asn). This variant is present in population databases (rs539326697, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212844). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001271170	SCV003829291	uncertain significance	Classic homocystinuria	2019-10-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001271170	SCV004047250	uncertain significance	Classic homocystinuria		criteria provided, single submitter	clinical testing	The missense variant c.397G>A (p.Asp133Asn) in CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Asp133Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01874% is reported in gnomAD. The amino acid Asp at position 133 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp133Asn in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Natera, Inc.	RCV001271170	SCV001452096	uncertain significance	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing