ClinVar Genomic variation as it relates to human health

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.).

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).

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.

This variant is associated with the following publications: (PMID: 22267502, 20981092, 21228398, 10338090)

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.

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.