Submissions for variant NM_004006.3(DMD):c.4373T>A (p.Phe1458Tyr)

gnomAD frequency: 0.00003  dbSNP: rs777274879

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757170	SCV000885303	likely benign	not provided	2018-04-11	criteria provided, single submitter	clinical testing	The c.4373T>A; p.Phe1458Tyr variant (rs777274879), to our knowledge, is not reported in the medical literature or gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with a Latino population frequency of 0.2% (identified on 43 out of 26,559 chromosomes, including 12 hemizygotes). The phenylalanine at position 1458 is highly conserved, considering 7 species, and computational analyses of the effects of the p.Phe1458Tyr variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the p.Phe1458Tyr variant is likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088088	SCV001001936	benign	Duchenne muscular dystrophy	2025-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174999	SCV001338496	benign	not specified	2020-04-02	criteria provided, single submitter	clinical testing	Variant summary: DMD c.4373T>A (p.Phe1458Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 182422 control chromosomes, predominantly at a frequency of 0.0016 within the Latino subpopulation in the gnomAD database, including 12 hemizygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 145 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathy phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.4373T>A in individuals affected with Dystrophinopathies 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, and both of them classified the variant as benign (1x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000757170	SCV001868184	benign	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002332536	SCV002629042	benign	Cardiovascular phenotype	2022-05-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Natera, Inc.	RCV001830659	SCV002085331	likely benign	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2020-04-13	no assertion criteria provided	clinical testing