Submissions for variant NM_004006.3(DMD):c.5324_5325delinsGT (p.Lys1775Ser)

dbSNP: rs1557303381

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000582079	SCV000751527	uncertain significance	Duchenne muscular dystrophy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with serine, which is neutral and polar, at codon 1775 of the DMD protein (p.Lys1775Ser). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 492824). 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 disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Ambry Genetics	RCV002350409	SCV002646818	uncertain significance	Cardiovascular phenotype	2023-04-14	criteria provided, single submitter	clinical testing	The c.5324_5325delAGinsGT variant (also known as p.K1775S), located in coding exon 37 of the DMD gene, results from an in-frame deletion of AG and insertion of GT at nucleotide positions 5324 to 5325. The lysine at codon 1775 is replaced by serine, an amino acid with dissimilar properties. However, this change also impacts the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, this allele has an overall frequency of 0.003% (7/204980) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was 0.037% (7/18995) of African alleles. These nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002476270	SCV002787423	uncertain significance	Becker muscular dystrophy; Duchenne muscular dystrophy; Dilated cardiomyopathy 3B	2022-01-07	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582079	SCV000692210	pathogenic	Duchenne muscular dystrophy	2015-04-15	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583809	SCV000692211	pathogenic	Becker muscular dystrophy	2015-04-15	no assertion criteria provided	clinical testing