ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.442G>A (p.Gly148Arg) (rs755952006)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411624 SCV000487113 likely pathogenic Classic homocystinuria 2016-10-10 criteria provided, single submitter clinical testing
Invitae RCV000411624 SCV001229019 pathogenic Classic homocystinuria 2019-04-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 148 of the CBS protein (p.Gly148Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs755952006, ExAC 0.009%). This variant has been observed to be homozygous or in combination with another CBS variant in several individuals affected with homocystinuria due to CBS deficiency (PMID: 16307898, 16479318, 15146473, 20694756). ClinVar contains an entry for this variant (Variation ID: 371512). This variant has been reported to affect CBS protein function (PMID: 20506325, 20490928, 16429402, 16307898). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193389 SCV001362174 pathogenic Homocystinuria 2019-01-31 criteria provided, single submitter clinical testing Variant summary: The variant, CBS c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain 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 244468 control chromosomes (gnomAD). The variant,c.442G>A has been reported in the literature in individuals affected with Homocystinuria (Katsushima_2005, Orendac_2004, Urreizti_2006). These data indicate that the variant is 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 <10% of normal activity (Kozich_2010, Katsushima_2005, Orendac_2004). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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