Submissions for variant NM_004006.3(DMD):c.7555G>A (p.Asp2519Asn)

gnomAD frequency: 0.00005  dbSNP: rs771877780

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489054	SCV000577805	pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing	The D2519N missense variant has been reported previously as de novo in a male with elevated CK level, calf hypertrophy, and a clinical diagnosis of Duchenne muscular dystrophy (Wang et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D2519N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Therefore, D2519N is interpreted as a pathogenic variant.
CeGaT Center for Human Genetics Tuebingen	RCV000489054	SCV001250360	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Department of Obstetrics, Zhejiang Provincial People's Hospital, Zhejiang Provincial People's Hospital	RCV001290983	SCV001429693	likely pathogenic	Duchenne muscular dystrophy	2020-08-16	criteria provided, single submitter	clinical testing	The D2519N missense variant was not observed in 1000 Genome database, ESP 6500 and genomAD. It was a presumed de novo variant in a female with elevated CK and harboring non-DMD family history. This substitution occurs at a position that is conserved across species (SIFT and PolyPhen predicted it deleterious and probably damaging). Therefore, D2519N is interpreted as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001290983	SCV001719769	benign	Duchenne muscular dystrophy	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526901	SCV001737647	uncertain significance	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: DMD c.7555G>A (p.Asp2519Asn) results in a conservative amino acid change located in the central rod domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 205897 control chromosomes, predominantly at a frequency of 0.0004 within the East Asian subpopulation in the gnomAD database, including 4 hemizygotes. The available data on variant occurrences in the general population suggest the variant could be a benign polymorphism found predominantly in individuals of East Asian ancestry, but are ultimately insufficient to allow any conclusion about variant significance. c.7555G>A has been reported in the literature as de novo in a male child affected with Duchenne Muscular Dystrophy (DMD) (Wang_2013) as well as in a female carrier with slightly elevated creatine kinase levels but no family history of DMD (Han_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33029525, 24770780). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three submitters classified the variant as pathogenic/likely pathogenic, two classified it as uncertain significance, and one submitter classified it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002395191	SCV002672855	uncertain significance	Cardiovascular phenotype	2022-06-25	criteria provided, single submitter	clinical testing	The p.D2519N variant (also known as c.7555G>A), located in coding exon 52 of the DMD gene, results from a G to A substitution at nucleotide position 7555. The aspartic acid at codon 2519 is replaced by asparagine, an amino acid with highly similar properties. This variant was described as de novo in one male reported to have symptoms of Duchenne muscular dystrophy (DMD), although clinical details were limited (Wang Y et al. Mol Genet Genomics, 2014 Oct;289:1013-21). This variant was also detected in a female with elevated creatine kinase (CK) levels who had no skeletal muscular or cardiac findings, and known family history of DMD (Han S et al. Biomed Res Int, 2020 Sep;2020:8396429). Based on data from gnomAD, the A allele has an overall frequency of 0.0029%( 6/205497) total alleles studied, with 4 hemizygotes observed. The highest observed frequency was 0.0403% (6/14879) of East Asian alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489054	SCV003800162	uncertain significance	not provided	2022-05-04	criteria provided, single submitter	clinical testing	The DMD c.7555G>A; p.Asp2519Asn variant (rs771877780) is reported in the literature as occurring de novo in a male diagnosed with muscular dystrophy and in a female with an increased CK undergoing carrier screening (Han 2020, Wang 2014). This variant is reported in the ClinVar database with conflicting classifications (Variation ID: 427170). This variant is found in the East Asian population with an allele frequency of 0.04% (6/14,879 alleles, including 4 hemizygotes) in the Genome Aggregation Database. The aspartic acid at codon 2519 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.254). Although the number of hemizygotes in the Genome Aggregation Database indicates this variant may be a rare benign variant, due to conflicting information, the clinical significance of the p.Asp2519Asn variant is uncertain at this time. References: Han S et al. Population-Wide Duchenne Muscular Dystrophy Carrier Detection by CK and Molecular Testing. Biomed Res Int. 2020 Sep 27;2020:8396429. PMID: 33029525. Wang Y et al. Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy. Mol Genet Genomics. 2014 Oct;289(5):1013-21. PMID: 24770780.