Submissions for variant NM_004006.3(DMD):c.8668G>A (p.Glu2890Lys)

dbSNP: rs398124076

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003041431	SCV003444673	uncertain significance	Duchenne muscular dystrophy	2022-05-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2890 of the DMD protein (p.Glu2890Lys). This variant also falls at the last nucleotide of exon 58, which is part of the consensus splice site for this exon. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Duchenne muscular dystrophy (PMID: 19959795). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700919	SCV005204862	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: DMD c.8668G>A (p.Glu2890Lys) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182945 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8668G>A has been reported in the literature in individuals affected with Duchenne Muscular Dystrophy (e.g. Torella_2010, Nicolas_2012). 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: 22776072, 19959795). ClinVar contains an entry for this variant (Variation ID: 2138506). Based on the evidence outlined above, the variant was classified as uncertain significance.