Submissions for variant NM_000071.3(CBS):c.304A>C (p.Lys102Gln)

gnomAD frequency: 0.01138  dbSNP: rs34040148

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224394	SCV000167573	benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22267502, 20981092, 21228398, 10338090)
Eurofins Ntd Llc (ga)	RCV000178036	SCV000230022	benign	not specified	2015-02-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000178036	SCV000268833	benign	not specified	2015-07-16	criteria provided, single submitter	clinical testing	p.Lys102Gln in exon 4 of CBS: This variant is not expected to have clinical sign ificance because it has been identified in 4% (415/10368) of African chromosomes by the Exome Aggregation Consortium (ExAC,http://exac.broadinstitute.org; dbSNP rs34040148).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224394	SCV000281546	benign	not provided	2015-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228454	SCV000283386	benign	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000233317	SCV000436230	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Ambry Genetics	RCV002312820	SCV000738386	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-08-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
SIB Swiss Institute of Bioinformatics	RCV000233317	SCV000803598	benign	Classic homocystinuria	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Homocystinuria due to cystathionine beta-synthase deficiency, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224394	SCV000883541	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178036	SCV002547804	benign	not specified	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: CBS c.304A>C (p.Lys102Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 251336 control chromosomes, predominantly at a frequency of 0.04 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.304A>C in individuals affected with Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277188	SCV002566483	likely benign	Connective tissue disorder	2019-03-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000224394	SCV005206372	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000233317	SCV001452101	benign	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000178036	SCV001917100	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224394	SCV001931636	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000178036	SCV002037048	benign	not specified		no assertion criteria provided	clinical testing