ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7897T>G (p.Leu2633Val) (rs587779868)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115257 SCV000149166 uncertain significance not provided 2013-10-09 criteria provided, single submitter clinical testing This variant is denoted c.7897T>G at the cDNA level or p.Leu2633Val (L2633V) at the protein level. This variant results in the replacement of a Leucine codon (TTA) with a Valine codon (GTA) at amino acid position 2633 of the ATM gene. The Leu2633Val missense substitution has not been published as a mutation, nor has it been reported as a polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports Leu2633Val was not observed in approximately 6500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The Leu2633Val variant is a conservative substitution as a neutral Leucine residue is replaced by a neutral Valine residue at a position that is evolutionarily moderately conserved across species and is not located in a known functional domain. Additionally, in silico models are consistent in their prediction of a benign effect on protein structure and function. Based on the currently available information, we consider Leu2633Val to be a variant of uncertain significance.
Invitae RCV000475783 SCV000546707 uncertain significance Ataxia-telangiectasia syndrome 2016-07-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 2633 of the ATM protein (p.Leu2633Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127451). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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