ClinVar Miner

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

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Total submissions: 6
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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 The p.I323V variant (also known as c.967A>G), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 967. The isoleucine at codon 323 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in ataxia-telangiectasia (A-T) patients (Li M et al. Am J Med Genet. 2000; 92:170-7; Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174). Functional analyses of cells generated from A-T patients with this alteration have shown loss of ATM protein and defects in DNA repair or survival following ionizing radiation (Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174). This alteration is predicted to have some functional significance based on a bioinformatics program integrating multiple in silico methods (George Priya Doss C and Rajith B. PLoS ONE. 2012; 7:e34573). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be possibly damaging but tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 Health, Inc RCV000129488 SCV000913539 pathogenic Hereditary cancer-predisposing syndrome 2020-09-23 criteria provided, single submitter clinical testing This c.967A>G variant is predicted to replace isoleucine with valine at codon 323 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site. An RNA study using cells from a homozygous individual has shown that this variant results in two transcripts: the major one with an out‚Äêof‚Äêframe deletion including 99 bases of exon 8 and the entire exon 9 (r.967_1235del, p.Ile323Alafs*17) and the minor transcript with only in‚Äêframe deletion of 99 bases of exon 8 (r.967_1065del, p.Ile323_Gln355del) (PMID: 31050087). The transcript with the r.967A>G (p.Ile323Val) missense variant was not detected in this study, indicating almost complete splicing defect due to the c.967A>G variant. This variant has been reported in multiple individuals affected with ataxia telangiectasia in compound heterozygous state with another pathogenic variant (PMID: 10817650, 23652012, 27664052) or in homozygous state (PMID: 31050087). This variant has been identified in 2/251086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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.
Johns Hopkins Genomics, Johns Hopkins University RCV000675169 SCV001573160 pathogenic Ataxia-telangiectasia syndrome 2021-04-07 criteria provided, single submitter clinical testing

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