ClinVar Miner

Submissions for variant NM_000117.2(EMD):c.449+5G>A (rs370840449)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183442 SCV000235902 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing The c.449+5 G>A variant in the EMD gene has not been reported as pathogenic or benign to our knowledge. This variant is located within the first five nucleotides of intron 5 and occurs at a nucleotide that is conserved across species. Two of three splice prediction algorithms predict c.449+5 G>A destroys the canonical splice donor site of intron 5 and may result in abnormal gene splicing. Additionally, other splice variants within the canonical splice site of intron 5 (c.449+1 G>A, c.449+2 T>C) have been reported in the Human Gene Mutation Database in association with Emery-Dreifuss muscular dystrophy (EDMD) (Stenson et al., 2014). However, in the absence of functional mRNA studies, the physiological consequence of the c.449+5 G>A variant remains to be definitively determined. Furthermore, c.449+5 G>A has also been observed in four apparently unaffected hemizygous individuals; three individuals observed in the Genome Aggregation Database (Lek et al., 2016) and one other unrelated male referred for genetic testing at GeneDx.
Invitae RCV000804499 SCV000944411 uncertain significance Emery-Dreifuss muscular dystrophy 1, X-linked 2018-10-30 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the EMD gene. It does not directly change the encoded amino acid sequence of the EMD protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs370840449, ExAC 0.01%). This variant has not been reported in the literature in individuals with EMD-related disease. ClinVar contains an entry for this variant (Variation ID: 201773). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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