VCV000179133.9 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 179133 Accession: VCV000179133.9

Type and length

Microsatellite, 5 bp

Location

Cytogenetic: Xq28 X: 154381072-154381073 (GRCh38) [ NCBI UCSC ] X: 153609432-153609433 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 31, 2015	Feb 14, 2024	Apr 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000117.3:c.650_654dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000108.1:p.Gln219fs	frameshift
NM_000117.2:c.650_654dupTGGGC		frameshift
NC_000023.11:g.154381077TGGGC[3]
NC_000023.10:g.153609437TGGGC[3]
NG_008677.1:g.11642TGGGC[3]
LRG_745:g.11642TGGGC[3]

... more HGVS ... less HGVS

Protein change

Q219fs

Other names

p.Gln219TrpfsX20

Canonical SPDI

NC_000023.11:154381072:GGGCTGGGCTGGGC:GGGCTGGGCTGGGCTGGGC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA273589 dbSNP: rs730880352 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EMD		-	-	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neuromuscular disease	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2013	RCV000155918.5
X-linked Emery-Dreifuss muscular dystrophy	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 18, 2023	RCV001850141.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Emery-Dreifuss muscular dystrophy 1, X-linked Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580839.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1_mod, PS4_MOD, PM2_SUP, PP1	Number of individuals with the variant: 1 Sex: male
Pathogenic (Apr 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	X-linked Emery-Dreifuss muscular dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002234004.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 8595406‚ 17355552‚ 18646565‚ 31474437 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 19, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Neuromuscular disease (X-linked inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205629.4 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Publications: PubMed (3) PubMed: 10220866‚ 17355552‚ 8595406 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Emery-Dreifuss muscular dystrophy 1, X-linked (X-linked recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002766777.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 8595406‚ 17355552 Comment: 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 … (more) 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 (less)

Comment:

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.

Comment:

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.

Comment:

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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
X-linked Emery-Dreifuss muscular dystrophy manifesting with adult onset axial weakness, camptocormia, and minimal joint contractures.	Brisset M	Neuromuscular disorders : NMD	2019	PMID: 31474437
Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan.	Astejada MN	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2007	PMID: 18646565
Co-morbidity of Emery-Dreifuss muscular dystrophy and a congenital myasthenic syndrome possibly affecting the phenotype in a large Bedouin kindred.	Ifergane G	European journal of neurology	2007	PMID: 17355552
Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy.	Funakoshi M	Neuromuscular disorders : NMD	1999	PMID: 10220866
Identification of novel mutations in three families with Emery-Dreifuss muscular dystrophy.	Klauck SM	Human molecular genetics	1995	PMID: 8595406

Text-mined citations for rs730880352 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730880352 ...