ClinVar Miner

Submissions for variant NM_000254.3(MTR):c.1310C>A (p.Ser437Tyr)

gnomAD frequency: 0.00006  dbSNP: rs368619885
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000277903 SCV000356032 uncertain significance Disorders of Intracellular Cobalamin Metabolism 2017-04-28 criteria provided, single submitter clinical testing The MTR c.1310C>A (p.Ser437Tyr) missense variant has been reported in one study in which it was identified in a compound heterozygous state with a second missense variant in one individual with methylcobalamin deficiency G disorder (Watkins et al. 2002). The p.Ser437Tyr variant was absent from 50 controls and is reported at a frequency of 0.00012 in the European-American population of the Exome Sequencing Project, but this is based on one allele only so is presumed to be rare. Based on the limited evidence, the p.Ser437Tyr variant is classified as a variant of unknown significance but suspicious for pathogenicity for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV001753754 SCV001986017 uncertain significance not provided 2021-02-02 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12068375)
Labcorp Genetics (formerly Invitae), Labcorp RCV001850550 SCV002289929 uncertain significance Methylcobalamin deficiency type cblG 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 437 of the MTR protein (p.Ser437Tyr). This variant is present in population databases (rs368619885, gnomAD 0.005%). This missense change has been observed in individual(s) with methylcobalamin deficiency G disorder (PMID: 12068375). ClinVar contains an entry for this variant (Variation ID: 296563). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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