ClinVar Genomic variation as it relates to human health

The c.967A>G variant (also known as p.I323V), 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 individuals diagnosed with ataxia-telangiectasia (AT) (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; Berland et al J Allergy Clin Immunol 2019 01;143(1):325-334.e2). This variant was also detected in one individual diagnosed with ovarian cancer (Sugino et al Sci Rep 2019 11;9(1):17808) and one individual diagnosed with pancreatic cancer (Cremin et al Cancer Med 2020 06;9(11):4004-4013). Functional analyses of cells generated from individuals diagnosed with AT 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 nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Patient-derived cells from a homozygous A-T patient, also harboring another homozygous ATM variant, demonstrated aberrant splicing, resulting an out-of-frame transcript leading to protein truncation (Fievet et al., 2019); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23652012, 22529920, 26659599, 24145436, 10817650, 26246501, 31050087, 29906526, 27664052, 35245693, 31780705, 32255556)

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the ATM protein (p.Ile323Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 101 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781511, gnomAD 0.003%). This missense change has been observed in individuals with ataxia telangiectasia (PMID: 10817650, 23652012, 27664052, 31050087). ClinVar contains an entry for this variant (Variation ID: 141123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 8 (Invitae). For these reasons, this variant has been classified as Pathogenic.

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-of-frame 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-frame 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.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 27664052]. Functional studies indicate this variant impacts protein function [PMID: 27664052].