X-154379754-GC-GCC

Variant names:

• chrX-154379754-G-GC
• rs876661345
• NM_000117.3:c.153dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000117.3(EMD):​c.153dupC​(p.Ser52GlnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,711 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EMD NM_000117.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.25
• Publications: 3 publications found

Genes affected

EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]

EMD Gene-Disease associations (from GenCC):

• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154379754-G-GC is Pathogenic according to our data. Variant chrX-154379754-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 234991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.153dupC	p.Ser52GlnfsTer9	frameshift_variant	Exon 2 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.153dupC	p.Ser52GlnfsTer9	frameshift_variant	Exon 2 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093711 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360299

African (AFR) AF: 0.00 AC: 0 AN: 26223

American (AMR) AF: 0.0000289 AC: 1 AN: 34623

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19269

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 53647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840604

Other (OTH) AF: 0.00 AC: 0 AN: 45899

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jul 31, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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). -

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. Loss-of-function variants in EMD are known to be pathogenic (PMID: 24365856). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy (PMID: 17620497, 21697856). This variant is also known as c.153_154insC. ClinVar contains an entry for this variant (Variation ID: 234991). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jul 25, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.153dupC pathogenic mutation, located in coding exon 2 of the EMD gene, results from a duplication of cysteine at position 153, causing a translational frameshift with a predicted premature stop codon. In one study, this alteration was identified in a 9 year old boy with clinical diagnosis of limb girdle muscular dystrophy (LGMD), who had absence of emerin on immunohistochemical staining of skeletal muscle biopsy tissue. Clinical features at age 9 included Gowers sign, waddling gait, proximal dominant limb muscle weakness and atrophy, transient sinus arrhythmia on electrocardiogram, but no joint contractures and a normal echocardiogram (Ura etal. Arch. Neurol. 2007;64:1038-1041). This alteration was also identified in a series of patients referred for genetic testing due to a suspected diagnosis of Emery-Dreiffuss muscular dystrophy (EDMD). Authors identify exon 2 as a hot spot for mutations in the EMD gene (Brown etal. J. Hum. Genet. 2011;56:589-594). In addition, alterations causing a translational frameshift are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). Based on available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876661345; hg19: chrX-153608114; COSMIC: COSV100877422; COSMIC: COSV100877422;