Submissions for variant NM_000071.3(CBS):c.856A>G (p.Ile286Val)

gnomAD frequency: 0.00020  dbSNP: rs147040567

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000731875	SCV000249695	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517999	SCV000769932	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the CBS protein (p.Ile286Val). This variant is present in population databases (rs147040567, 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: 212855). 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.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000648120	SCV000804339	uncertain significance	Classic homocystinuria	2017-10-06	criteria provided, single submitter	provider interpretation	This 6 year old male with global developmental delays is a compound heterozygote for 2 VUSs in the CBS gene (p.Glu283Lys and p.Ile286Val). The p.Ile286Val variant is present in the gnomAD non-Finnish European population at a frequency of 0.02%. Computational models predict it to benign. He has normal stature (30%tile). Subsequent clinical testing showed normal plasma homocysteine and methionine levels.
Eurofins Ntd Llc (ga)	RCV000731875	SCV000859738	uncertain significance	not provided	2018-02-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000648120	SCV001303266	uncertain significance	Classic homocystinuria	2017-04-28	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.
Ambry Genetics	RCV002444786	SCV002680385	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-17	criteria provided, single submitter	clinical testing	The p.I286V variant (also known as c.856A>G), located in coding exon 8 of the CBS gene, results from an A to G substitution at nucleotide position 856. The isoleucine at codon 286 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000648120	SCV002777121	uncertain significance	Classic homocystinuria	2021-10-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000648120	SCV001462115	uncertain significance	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing