ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.967A>G (p.Ile323Val) (rs587781511)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129488 SCV000184259 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
GeneDx RCV000486107 SCV000568314 likely pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.967A>G at the cDNA level, p.Ile323Val (I323V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has been observed in at least two individuals with Ataxia-Telangiectasia (A-T) (Li 2000, Lee 2013). In vivo functional studies performed in a cell line created from the fibroblasts of a patient with A-T, compound heterozygous for ATM Ile323Val and an ATM frameshift variant, showed no ATM protein expression (Lee 2013). ATM Ile323Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ile323Val occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a cryptic splice donor site upstream of the natural donor site for intron 8 and lead to abnormal splicing. Based on the currently available evidence, we consider ATM Ile323Val to be a likely pathogenic variant.
Counsyl RCV000675169 SCV000800790 likely pathogenic Ataxia-telangiectasia syndrome 2017-09-28 criteria provided, single submitter clinical testing
Color RCV000129488 SCV000913539 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing
Invitae RCV000675169 SCV001385997 pathogenic Ataxia-telangiectasia syndrome 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 323 of the ATM protein (p.Ile323Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ataxia telangiectasia (PMID: 10817650, 27664052, 23652012, 31050087). ClinVar contains an entry for this variant (Variation ID: 141123). 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 and their clinical significance is uncertain. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 31050087). For these reasons, this variant has been classified as Pathogenic.

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