ClinVar Miner

Submissions for variant NM_000117.3(EMD):c.399+1G>T

dbSNP: rs2148128554
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001994790 SCV002233851 pathogenic X-linked Emery-Dreifuss muscular dystrophy 2021-05-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the EMD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EMD are known to be pathogenic (PMID: 24365856). This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with Emery–Dreifuss muscular dystrophy (PMID: 9536090). 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. For these reasons, this variant has been classified as Pathogenic.
Department of Medical Genetics, National Institute of Health RCV001994790 SCV002564382 pathogenic X-linked Emery-Dreifuss muscular dystrophy 2022-08-19 no assertion criteria provided clinical testing A non-consanguineous 40-year-old patient, second of a sibling of 5 was referred for genetic investigation. At the age of 5, he had slowly progressive muscle weakness and wasting with humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, leading to loss of deambulation at age of 13. At 30-year-old, he was diagnosed with atrial flutter that required pacemaker implantation. Two deceased maternal uncles had similar features. NGS sequencing of a custom gene panel lead to the identification of a deleterious hemizygous splicing mutation, NM_000117.3(EMD):c.399+1G>T in the EMD gene. This splice variant identified was only once reported in Clinvar in a patient with EDMD condition. Carrier status of the EMD mutation was investigated in several relatives at risk.

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