Submissions for variant NM_001386795.1(DTNA):c.2039G>A (p.Arg680Gln)

gnomAD frequency: 0.00034  dbSNP: rs138143719

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171939	SCV000050938	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000608722	SCV000743514	likely benign	Left ventricular noncompaction 1	2016-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000608722	SCV002143684	uncertain significance	Left ventricular noncompaction 1	2024-12-18	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 653 of the DTNA protein (p.Arg653Gln). This variant is present in population databases (rs138143719, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 191656). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307432	SCV002600856	likely benign	not specified	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: DTNA c.1958G>A (p.Arg653Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251422 control chromosomes. The observed variant frequency is approximately 48 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNA causing Left Ventricular Noncompaction phenotype (3.1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1958G>A in individuals affected with Left Ventricular Noncompaction and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000608722	SCV000733791	likely benign	Left ventricular noncompaction 1		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171939	SCV001980236	likely benign	not provided		no assertion criteria provided	clinical testing