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 uncertain significance Homocystinuria due to CBS deficiency 2018-06-12 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). Experimental studies have shown that this missense change disrupts CBS protein function (PMID: 22267502). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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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