ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9073del (p.Val3025fs) (rs1555151928)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000628091 SCV000748981 pathogenic Ataxia-telangiectasia syndrome 2018-03-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ATM gene (p.Val3025Cysfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acids of the ATM protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. This variant is expected to disrupt the FATC domain (amino acids 3024-3056). Loss or disruption of this domain results in impaired interaction with Tip60, suppression of ATM kinase activity, impaired cellular response to DNA damage, and telomere maintenance defects (PMID: 23671275, 16603769, 26246601). A nonsense variant occurring in this domain (c.9139C>T (p.Arg3047*)) has been determined to be pathogenic, with observations in multiple individuals with ataxia-telangiectasia (PMID: 8755918, 19691550, 18560558, 10980530, 26628246), and an experimental study that has shown this variant disrupts ATM kinase activity (PMID: 19431188). This suggests that the FATC domain is critical for ATM protein function and that other variants that disrupt this region may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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