ClinVar Miner

Submissions for variant NM_000117.2(EMD):c.153dup (p.Ser52fs) (rs876661345)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246169 SCV000318752 pathogenic Cardiovascular phenotype 2013-07-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000697180 SCV000825777 pathogenic Emery-Dreifuss muscular dystrophy 1, X-linked 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser52Glnfs*9) in the EMD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy (PMID: 21697856, 17620497). This variant is also known as c.153_154insC in the literature. ClinVar contains an entry for this variant (Variation ID: 234991). Loss-of-function variants in EMD are known to be pathogenic (PMID: 24365856). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223909 SCV000280100 pathogenic not provided 2013-07-31 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the information below, we consider this variant very likely pathogenic. The c.153dupC EMD variant, located on exon 2, results from a duplication of cysteine at position 153, causing a translational frameshift with a predicted premature stop codon. This variant was identified in a 9 year old boy with a clinical diagnosis of limb girdle muscular dystrophy, with absence of emerin on IHC staiining of skeletal muscle biopsy tissue (Ura et al., 2007). This patient had a normal echocardiogram. Brown and colleagues (Brown et al., 2011) studied 225 participants referred for genetic screening following a clinical diagnosis of EDMD, limb-girdle muscular dystrophy, Becker muscular dystrophy or FSHD. FHL1, SYNE1 and SYNE2 mutations were not screened, as the screening programme predated linkage of these genes to the EDMD phenotype. They reported eight novel mutations including six frameshift mutations (p.D9GfsX24, p.F39SfsX17, p.R45KfsX16, p.F190YfsX19, p.R203PfsX34 and p.R204PfsX7) and two non-sense mutations (p.S143X and p.W200X) Brown et al. also identified exon 2 as a hot spot for mutations in the EMD gene. The three most common mutations identified in exon 2 were at codon 51 resulting in p.S52AfsX13 (4 hits; stop at codon 64) and p.Y34X (3 hits). Four of the 18 (22%) probands had mutations in exon 2, of which two are novel but with one also targeting residue S52. Frameshift mutations in the EMD gene have been previously shown to allow modified emerin expression, suggest the shortest length required for protein expression is 208 residues, which is 94% (208/221) of the nucleoplasmic domain length, as shown by the in vivo expression of the p.P169RfsX40 mutation. From this, we can predict that three of our novel mutations (p.F190YfsX19, p.R203PfsX34 and p.R204PfsX7) will express truncated forms of erroneous protein, with the remaining mutations preventing protein expression. There is no variation at codon 52 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/1/13).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.