ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.192del (p.Leu64fs) (rs878853490)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231922 SCV000282885 pathogenic Ataxia-telangiectasia syndrome 2017-03-30 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 4 of the ATM mRNA (c.192delA), causing a frameshift at codon 64. This creates a premature translational stop signal (p.Leu64Phefs*12) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000231922 SCV000486595 likely pathogenic Ataxia-telangiectasia syndrome 2016-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000231922 SCV000918565 likely pathogenic Ataxia-telangiectasia syndrome 2018-09-28 criteria provided, single submitter clinical testing Variant summary: ATM c.192delA (p.Leu64PhefsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Glu73fsX26, p.Tyr171X, p.Tyr264fsX12). The variant was absent in 273852 control chromosomes. To our knowledge, no occurrence of c.192delA in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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