ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3848T>C (p.Leu1283Pro) (rs730881389)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212004 SCV000209783 likely pathogenic not specified 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.3848T>C at the cDNA level, p.Leu1283Pro (L1283P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). This variant has been observed to co-occur with another ATM variant in at least three individuals with ataxia-telangiectasia and has been shown to result in no detectable ATM protein and absent kinase activity (Sun 2002, Buzin 2003, Pietrucha 2010, Soukupova 2011). ATM Leu1283Pro was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Leu1283Pro occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider this variant to be likely pathogenic.
Ambry Genetics RCV000159763 SCV000217390 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-10 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence
Invitae RCV000474326 SCV000546658 likely pathogenic Ataxia-telangiectasia syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1283 of the ATM protein (p.Leu1283Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (rs730881389, ExAC no frequency). This variant has been observed with other likely pathogenic or pathogenic variants in individuals affected with ataxia-telangiectasia (PMID: 12072877, 21833744). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 181994). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000159763 SCV001359401 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-02 criteria provided, single submitter clinical testing

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