ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1838T>G (p.Val613Gly)

gnomAD frequency: 0.00001  dbSNP: rs762018538
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472274 SCV000547076 uncertain significance Ataxia-telangiectasia syndrome 2021-08-24 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 613 of the ATM protein (p.Val613Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407687). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000572810 SCV000660488 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing The p.V613G variant (also known as c.1838T>G), located in coding exon 11 of the ATM gene, results from a T to G substitution at nucleotide position 1838. The valine at codon 613 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000572810 SCV000682005 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194266 SCV001363658 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: ATM c.1838T>G (p.Val613Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245726 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1838T>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001584149 SCV001817923 uncertain significance not provided 2020-01-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with features of Cowden or Bannayan-Riley-Ruvalcaba syndrome (Yehia 2018); This variant is associated with the following publications: (PMID: 29684080)
Genetic Services Laboratory,University of Chicago RCV001584149 SCV002064364 likely pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing This sequence change, c.1838T>G in exon 12, results in an amino acid change, p.Val613Gly, was identified with another pathogenic ATM variant in a patient. The p.Val613Gly change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL, in silico splice prediction tools) provide contradictory results for the p.Val613Gly substitution. This sequence change is absent from the gnomAD database. The p.Val613Gly amino acid change occurs in a region of the ATM gene where other missense sequence changes have been described in patients with ATM-related disorders. This sequence change, in trans configuration with the p.Glu937Alafs*33 pathogenic sequence change, is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Sema4,Sema4 RCV000572810 SCV002533431 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-15 criteria provided, single submitter curation
Natera, Inc. RCV000472274 SCV002076145 uncertain significance Ataxia-telangiectasia syndrome 2021-10-19 no assertion criteria provided clinical testing

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