Submissions for variant NM_000071.3(CBS):c.1072G>A (p.Val358Met)

gnomAD frequency: 0.00013  dbSNP: rs148589243

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000420634	SCV000225480	uncertain significance	not provided	2015-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000420634	SCV000249707	likely benign	not provided	2020-12-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: no PMID)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000420634	SCV000510675	uncertain significance	not provided	2016-07-06	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV002517673	SCV000543512	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-07-30	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 358 of the CBS protein (p.Val358Met). This variant is present in population databases (rs148589243, gnomAD 0.02%). 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: 193971). 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.
Illumina Laboratory Services, Illumina	RCV000474043	SCV001300404	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000420634	SCV002048346	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing	The CBS c.1072G>A; p.Val358Met variant (rs148589243), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 193971). This variant is found in the general population with an overall allele frequency of 0.01 % (28/ 271,082 alleles) in the Genome Aggregation Database. The valine at codon 358 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.565). Due to limited information, the clinical significance of the p.Val358Met variant is uncertain at this time.
Ambry Genetics	RCV002415740	SCV002717559	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-10	criteria provided, single submitter	clinical testing	The c.1072G>A (p.V358M) alteration is located in exon 12 (coding exon 10) of the CBS gene. This alteration results from a G to A substitution at nucleotide position 1072, causing the valine (V) at amino acid position 358 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000474043	SCV001455974	uncertain significance	Classic homocystinuria	2020-01-06	no assertion criteria provided	clinical testing