Submissions for variant NM_004006.3(DMD):c.3281T>C (p.Leu1094Ser)

gnomAD frequency: 0.00009  dbSNP: rs876657778

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216308	SCV000271653	uncertain significance	not specified	2015-04-28	criteria provided, single submitter	clinical testing	The p.Leu1094Ser variant in DMD has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to asses s its frequency. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu1094Ser variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000727493	SCV000709107	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV001237021	SCV001409768	uncertain significance	Duchenne muscular dystrophy	2022-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1094 of the DMD protein (p.Leu1094Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 228580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Revvity Omics, Revvity	RCV000727493	SCV003829504	uncertain significance	not provided	2019-04-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000727493	SCV001549845	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DMD p.Leu971Ser variant was not identified in the literature but was identified in dbSNP (ID: rs876657778) and ClinVar (classified as uncertain significance by EGL Genetics and Laboratory for Molecular Medicine). The variant was identified in control databases in 4 of 136057 chromosomes at a frequency of 0.0000294 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the African population in 4 of 15041 chromosomes (freq: 0.000266), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Leu971 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact to the protein; however this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV001828071	SCV002085468	uncertain significance	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2020-05-06	no assertion criteria provided	clinical testing