ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.742C>G (p.Arg248Gly)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002601700 SCV002949895 uncertain significance Ataxia-telangiectasia syndrome 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 248 of the ATM protein (p.Arg248Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebellar ataxia (PMID: 3149931). ClinVar contains an entry for this variant (Variation ID: 1917922). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV002601700 SCV004047426 likely pathogenic Ataxia-telangiectasia syndrome criteria provided, single submitter clinical testing The missense variant c.742C>G (p.Arg248Gly) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, another variant in the ATM gene at the same position c.742C>T (p.Arg248Ter) has been reported in individuals affected with ataxia telangiectasia (Sasaki et al. 1998, Mitui et al. 2005). The c.742C>T (p.Arg248Ter) variant creates a premature translational stop signal (p.Arg248*) in the ATM gene which is expected to result in an absent or disrupted protein product whereas the variant c.742C>G (p.Arg248Gly) causes a missense change. The c.742C>G (p.Arg248Gly) variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 248 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change c.742C>G (p.Arg248Gly) in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

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