ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.457G>A (p.Gly153Arg) (rs745704046)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000689266 SCV000816908 pathogenic Classic homocystinuria 2019-08-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 153 of the CBS protein (p.Gly153Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs745704046, ExAC 0.01%). This variant has been observed to segregate with homocystinuria in a family (PMID: 21517828). This variant has also been observed in an individual with intellectual disability, lens dislocation, marfanoid habitus and elevated levels of total homocysteine and methionine in plasma, findings that are highly specific for homocystinuria due to CBS deficiency (PMID: 30246729). Experimental studies have shown that this missense change disrupts CBS protein function (PMID: 22267502, external communication Fritz Roth lab). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781198 SCV000919083 likely pathogenic Homocystinuria 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The CBS c.457G>A (p.Gly153Arg) variant involves the alteration of a conserved nucleotide that lies within the pyridoxal-phosphate dependent enzyme domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/156632 control chromosomes at a frequency of 0.0000064, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been reported in a Saudi Arabian family, where two affected patients were homozygous for the variant, which was inherited from unaffected consanguineous heterozygous parents (Zaidi_2012). Additionally, two functional studies in yeast suggest that the variant may impact protein function (Wei_2010, Mayfield_2012). Taken together, this variant is classified as likely pathogenic.

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