Submissions for variant NM_001386795.1(DTNA):c.1000G>A (p.Val334Met)

gnomAD frequency: 0.00120  dbSNP: rs148123045

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171931	SCV000050933	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039666	SCV000063355	uncertain significance	not specified	2012-07-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val334Ile varia nt in DTNA has been previously identified in one infant with HCM (LMM unpublishe d data). This variant is present at low frequency in various cohorts, the highes t being 0.16% (7/4406) in a broad African American cohort screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs148123045). Computational analyses (biochemical amino acid properties, conservation, AlignG VGD, PolyPhen2, and SIFT) suggest that the Val334Ile variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, although these data support that the Val334Ile variant may be b enign, additional studies are needed to fully assess its clinical significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171931	SCV000697862	benign	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The variant c.1000G>A (p.Val334Ile) in DTNA gene involves a conserved nucleotide with 3/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large and broad control population from ExAC with an allele frequency of 117/121378 (1/1037), which exceeds the estimated maximum expected allele frequency for a pathogenic DTNA variant of 1/40000. The variant of interest has been reported in individuals undergoing exome sequencing with limited information (i.e. information about co-occurrence and/or co-segregation data). In addition, multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance," although it should be noted the classification evaluation occurred prior to the availablity of the ExAC dataset. Therefore, taken all available lines of evidence into consideration, the variant of interest is classified as Benign.
GeneDx	RCV000039666	SCV000729094	likely benign	not specified	2017-06-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001001740	SCV000764381	benign	Left ventricular noncompaction 1	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001740	SCV001159343	likely benign	Left ventricular noncompaction 1	2018-09-28	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000171931	SCV001742897	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000039666	SCV001926664	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171931	SCV001968856	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944929	SCV004764186	likely benign	DTNA-related disorder	2024-06-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).