ClinVar Genomic variation as it relates to human health

This variant is denoted ATM c.1463G>A at the cDNA level and p.Trp488Ter (W488X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported patients with classical ataxia-telangiectasia (Cavalieri 2006, Magliozzi 2006, Broccoletti 2011) and is considered pathogenic.

This sequence change creates a premature translational stop signal (p.Trp488*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 16941484, 17124347). ClinVar contains an entry for this variant (Variation ID: 246090). For these reasons, this variant has been classified as Pathogenic.

The c.1463G>A (p.Trp488*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the European (non-Finnish) subpopulation (PM2; http://gnomad.broadinstitute.org). It has been reported in one ataxia-telangiectasia proband in trans with a variant called “c.4436+2702del8526”, which corresponds to the in frame deletion of exons 30 to 34 (32 to 36 in the article’s numbering). This co-occurrence in trans with a likely pathogenic ATM variant awards c.1463G>A with 1 point as per ClinGen SVI Recommendation for in trans Criterion (PM3, PMID: 16941484). Moreover, cDNA studies in the compound heterozygous patient show only a deleted band compatible with the multi-exonic in-frame deletion. The lack of a normal band must mean that the non-deleted allele carrying the c.1463G>A (p.Trp488*) induces NMD, its non-expression demonstrated (PS3_Supporting). The c.1463G>A variant has also been detected in two other ataxia telangiectasia probands (PMID: 20840352, 17124347). In summary, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PM3 + PS3_Supporting (PMID: 33280026).

Variant summary: ATM c.1463G>A (p.Trp488X) 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 and a variant resulting in a termination codon at the same position, c.1464G>A (p.Trp488X), have been classified as pathogenic by our laboratory. The variant was absent in 251336 control chromosomes (gnomAD). c.1463G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia, including at least one case in which it was found to induce nonsense mediated decay (e.g. Cavalieri_2006, Magliozzi_2006, Broccoletti_2011). These data indicate that the variant is likely associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

The p.W488* pathogenic mutation (also known as c.1463G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1463. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This mutation has been identified in conjunction with an ATM gross deletion in an Italian individual diagnosed with ataxia-telangiectasia (Cavalieri S et al, Hum. Mutat. 2006 Oct; 27(10):1061). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.