X-154381072-GGGGCT-GGGGCTGGGCT

Position:

• chrX-154381072-GGGGCT-GGGGCTGGGCT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000117.3(EMD):​c.650_654dup​(p.Gln219TrpfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EMD NM_000117.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.180

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154381072-G-GGGGCT is Pathogenic according to our data. Variant chrX-154381072-G-GGGGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.650_654dup	p.Gln219TrpfsTer20	frameshift_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.650_654dup	p.Gln219TrpfsTer20	frameshift_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 18, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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 -

Neuromuscular disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 19, 2013

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880352; hg19: chrX-153609432;