Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV001144959 | SCV001305584 | uncertain significance | Seckel syndrome 1 | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Invitae | RCV001213729 | SCV001385378 | uncertain significance | not provided | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 635 of the ATR protein (p.Arg635Gln). This variant is present in population databases (rs202162034, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ATR-related conditions. ClinVar contains an entry for this variant (Variation ID: 900024). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
ARUP Laboratories, |
RCV001213729 | SCV002048472 | uncertain significance | not provided | 2021-10-25 | criteria provided, single submitter | clinical testing | The ATR c.1904G>A; p.Arg635Gln variant (rs202162034), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 900024). This variant is included in the IBD exomes browser database with a mild average odds ratio of 1.30 for IBD. (https://ibd.broadinstitute.org/) without any segregation and functional data. This variant is found in the general population with an overall allele frequency of 0.02% (66/282122 alleles) in the Genome Aggregation Database. The arginine at codon 635 is weakly conserved but computational analyses predict that this variant is neutral (REVEL: 0.084). Due to limited information, the clinical significance of the p.Arg635Gln variant is uncertain at this time. |
Genetic Services Laboratory, |
RCV001819849 | SCV002071014 | uncertain significance | not specified | 2021-09-23 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ATR gene demonstrated a sequence change, c.1904G>A, in exon 9 that results in an amino acid change, p.Arg635Gln. This sequence change has been described in the gnomAD database with a frequency of 0.038% in the non-Finnish European subpopulation (dbSNP rs202162034). The p.Arg635Gln change affects a poorly conserved amino acid residue located in a domain of the ATR protein that is known to be functional. The p.Arg635Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with ATR-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg635Gln change remains unknown at this time. |
Ambry Genetics | RCV002411649 | SCV002722663 | likely benign | Inborn genetic diseases | 2022-09-21 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Revvity Omics, |
RCV001213729 | SCV003834502 | uncertain significance | not provided | 2019-06-26 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
RCV003396772 | SCV004111503 | uncertain significance | ATR-related condition | 2022-12-07 | criteria provided, single submitter | clinical testing | The ATR c.1904G>A variant is predicted to result in the amino acid substitution p.Arg635Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-142275399-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |