ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1007G>A (p.Arg336His) (rs760417941)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409189 SCV000486656 likely pathogenic Classic homocystinuria 2016-07-14 criteria provided, single submitter clinical testing
Invitae RCV000409189 SCV000959121 pathogenic Classic homocystinuria 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 336 of the CBS protein (p.Arg336His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs760417941, ExAC 0.002%). This variant has been observed in individuals affected with homocystinuria (PMID: 9870207, 23974653, 25218699). ClinVar contains an entry for this variant (Variation ID: 371147). Experimental studies have shown that this missense change abolishes CBS activity (PMID: 22267502, 23974653, 16429402). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000409189 SCV001524387 pathogenic Classic homocystinuria 2020-08-18 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001584104 SCV001821464 pathogenic Homocystinuria 2021-08-08 criteria provided, single submitter clinical testing Variant summary: CBS c.1007G>A (p.Arg336His) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250592 control chromosomes. c.1007G>A has been reported in the literature in multiple individuals affected with B6 responsive Homocystinuria (example, Coude_1998, Mendes_2013, Alcaide_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 0.43% of normal CBS enzyme activity in an E. Coli based in-vitro system expressing mutant CBS proteins (Mendes_2014). Authors suggested misfolding and accelerated degradation as contributing to the mechanism of disease. Four 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 (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000409189 SCV001462107 pathogenic Classic homocystinuria 2020-09-16 no assertion criteria provided clinical testing

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