Submissions for variant NM_001184.4(ATR):c.4405A>G (p.Thr1469Ala)

gnomAD frequency: 0.00036  dbSNP: rs78895258

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429372	SCV000531492	uncertain significance	not provided	2016-09-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATR gene. The T1469A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T1469A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 3/1006 (0.3%) alleles from individuals of European background. The T1469A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000429372	SCV001215741	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1469 of the ATR protein (p.Thr1469Ala). This variant is present in population databases (rs78895258, gnomAD 0.1%). 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: 389064). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002506062	SCV002815827	uncertain significance	Seckel syndrome 1; Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126730	SCV003801566	uncertain significance	Seckel syndrome 1	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126731	SCV003801567	uncertain significance	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	2023-02-08	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000429372	SCV001797761	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000429372	SCV001974461	likely benign	not provided		no assertion criteria provided	clinical testing