ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.797G>A (p.Arg266Lys) (rs121964969)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469164 SCV000543517 pathogenic Classic homocystinuria 2016-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 266 of the CBS protein (p.Arg266Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (rs121964969, ExAC no frequency). This variant has been reported in the homozygous state in three individuals affected with pyridoxine-responsive CBS deficiency, and in the compound heterozygous state in several other affected individuals (PMID: 9361025). ClinVar contains an entry for this variant (Variation ID: 125). Experimental studies have shown that this missense change causes significantly reduced CBS activity and impairs the function of the protein (PMID: 9361025, 16619244, 22738154, 22267502, 22333527, 20506325, 22612060). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000621987 SCV000738475 pathogenic Cardiovascular phenotype 2017-06-16 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;Deficient protein function by in vitro/ex vivo assay
Counsyl RCV000469164 SCV000790684 likely pathogenic Classic homocystinuria 2017-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192721 SCV001361016 pathogenic Homocystinuria 2019-04-04 criteria provided, single submitter clinical testing Variant summary: CBS c.797G>A (p.Arg266Lys; p.R266K) results in a conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244782 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Homocystinuria (Guttormsen_2001, Moat_2004). These data indicate that the variant is very likely to be associated with disease. This mutation was well responsive to pyridoxine therapy (Guttormsen_2001). The effect of this variant on its enzymatic function has been characterized in detail. Several in vitro experiments suggest that this variant moderately reduce enzymatic activity (Chen _2006, Kozich _2010). However, using a transgenic mice over-expressing p.R266K variant, Gupta et al demonstrate that this mutation causes increased proteasomal degradation of the enzyme and the enzymatic activity is reduced to 2% of that found in livers expressing wild-type human CBS (Gupta_CBS_HM_2017). Three 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 pathogenic (X2) /likely pathogenic (X1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000147 SCV000020290 pathogenic Homocystinuria, pyridoxine-responsive 1997-12-01 no assertion criteria provided literature only

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