Submissions for variant NM_000117.3(EMD):c.650_654dup (p.Gln219fs)

dbSNP: rs730880352

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155918	SCV000205629	pathogenic	Neuromuscular disease	2013-07-19	criteria provided, single submitter	clinical testing	The Gln219fs variant in EMD has been reported in 3 males with Emery-Dreifuss mus cular dystrophy and segregated with disease in >5 affected males from 1 family ( variant reported as 1712_1713insTGGGC; Klauck 1995, Funakoshi 1999, Ifergane 200 7). This frameshift variant is predicted to alter the protein?s amino acid seque nce beginning at position 219 and lead to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Truncating variants in EMD are an established cause of EDMD. In s ummary, the Gln219fs variant meets our criteria for pathogenicity (http://pcpgm. partners.org/lmm) based on the predicted impact of the variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850141	SCV002234004	pathogenic	X-linked Emery-Dreifuss muscular dystrophy	2023-04-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179133). This variant is also known as 1712_1713ins TGGGC. This premature translational stop signal has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 8595406, 17355552, 18646565, 31474437). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln219Trpfs*20) in the EMD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the EMD protein.
MGZ Medical Genetics Center	RCV001850141	SCV002580839	likely pathogenic	X-linked Emery-Dreifuss muscular dystrophy	2022-02-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001850141	SCV002766777	pathogenic	X-linked Emery-Dreifuss muscular dystrophy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Emery-Dreifuss muscular dystrophy 1 (MIM#310300). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction with less than 1/3 of the protein sequence affected. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other truncation variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Emery-Dreifuss muscular dystrophy (PMID: 8595406, 17355552). A different c. change which results in the same p. change (c.640_644dup; p.Q219Wfs*20) has also been reported as likely pathogenic and pathogenic (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign