VCV000011176.10 - ClinVar

NM_000117.3(EMD):c.130C>T (p.Gln44Ter)

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.

(6)

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

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.130C>T (p.Gln44Ter)

Variation ID: 11176 Accession: VCV000011176.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154379737 (GRCh38) [ NCBI UCSC ] X: 153608097 (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	Jun 29, 2015	May 1, 2024	Oct 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000117.3:c.130C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000108.1:p.Gln44Ter	nonsense
NC_000023.11:g.154379737C>T
NC_000023.10:g.153608097C>T
NG_008677.1:g.10302C>T
LRG_745:g.10302C>T
LRG_745t1:c.130C>T	LRG_745p1:p.Gln44Ter

... more HGVS ... less HGVS

Protein change

Q44*

Other names

Q43*
NP_000108.1:p.Gln44*

Canonical SPDI

NC_000023.11:154379736:C:T

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: CA121384 OMIM: 300384.0006 dbSNP: rs132630262 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	540	807

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.
X-linked Emery-Dreifuss muscular dystrophy	Pathogenic (2)	criteria provided, single submitter	Oct 15, 2023	RCV000011926.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 25, 2023	RCV000078128.10
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Nov 17, 2020	RCV002381248.3

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.
Pathogenic (Oct 15, 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: SCV003445291.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24365856‚ 8595406 Comment: This sequence change creates a premature translational stop signal (p.Gln44) in the EMD gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln44) 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 individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 8595406). This variant is also known as 188C>T. ClinVar contains an entry for this variant (Variation ID: 11176). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 25, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000590864.1 First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015	Publications: PubMed (1) PubMed: 8595406 Observation 1: Age: 20-29 years Sex: male Observation 2: Age: 50-59 years Sex: male
Pathogenic (Sep 10, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000109966.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EMD Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Apr 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003921760.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function … (more) Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21993399, 30079154, 31718017, 10377322, 9472006, 9536090, 31683627, 8595406, 21697856, 10382909) (less)
Pathogenic (Nov 17, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002694311.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 21697856‚ 21993399‚ 30079154‚ 31718017‚ 8595406 Comment: The p.Q44* pathogenic mutation (also known as c.130C>T), located in coding exon 2 of the EMD gene, results from a C to T substitution at … (more) The p.Q44* pathogenic mutation (also known as c.130C>T), located in coding exon 2 of the EMD gene, results from a C to T substitution at nucleotide position 130. This mutation has been detected in males affected with Emery-Dreifuss muscular dystrophy, including several from a single family, as well as in at least one carrier female with cardiac findings (Brown CA et al. J Hum Genet, 2011 Aug;56:589-94; Carboni N et al. Neuromuscul Disord, 2012 Feb;22:152-8; Viggiano E et al. Genes (Basel), 2019 11;10:[Epub ahead of print]). In addition to the clinical data presented in the literature, this changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Oct 01, 1995)	no assertion criteria provided Method: literature only	EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032159.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016	Publications: PubMed (1) PubMed: 8595406 Comment on evidence: Klauck et al. (1995) identified novel mutations in 3 families with Emery-Dreifuss muscular dystrophy (310300). One of these was a C-to-T transition at nucleotide 188, … (more) Klauck et al. (1995) identified novel mutations in 3 families with Emery-Dreifuss muscular dystrophy (310300). One of these was a C-to-T transition at nucleotide 188, resulting in a change of codon 43 from CAG (gln) to a stop codon. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Gln44*) 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 individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 8595406). This variant is also known as 188C>T. ClinVar contains an entry for this variant (Variation ID: 11176). For these reasons, this variant has been classified as Pathogenic.

Comment:

Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21993399, 30079154, 31718017, 10377322, 9472006, 9536090, 31683627, 8595406, 21697856, 10382909)

Comment:

The p.Q44* pathogenic mutation (also known as c.130C>T), located in coding exon 2 of the EMD gene, results from a C to T substitution at nucleotide position 130. This mutation has been detected in males affected with Emery-Dreifuss muscular dystrophy, including several from a single family, as well as in at least one carrier female with cardiac findings (Brown CA et al. J Hum Genet, 2011 Aug;56:589-94; Carboni N et al. Neuromuscul Disord, 2012 Feb;22:152-8; Viggiano E et al. Genes (Basel), 2019 11;10:[Epub ahead of print]). In addition to the clinical data presented in the literature, this changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers.	Viggiano E	Genes	2019	PMID: 31718017
Obesity and pericallosal lipoma in X-linked emery-dreifuss muscular dystrophy: A case report - Does Emerin play a role in adipocyte differentiation?	Spanu F	World journal of radiology	2018	PMID: 30079154
Emerin in health and disease.	Koch AJ	Seminars in cell & developmental biology	2014	PMID: 24365856
Cardiac and muscle imaging findings in a family with X-linked Emery-Dreifuss muscular dystrophy.	Carboni N	Neuromuscular disorders : NMD	2012	PMID: 21993399
Novel and recurrent EMD mutations in patients with Emery-Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot.	Brown CA	Journal of human genetics	2011	PMID: 21697856
Identification of novel mutations in three families with Emery-Dreifuss muscular dystrophy.	Klauck SM	Human molecular genetics	1995	PMID: 8595406
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EMD	-	-	-	-

Text-mined citations for rs132630262 ...

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.130C>T (p.Gln44Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs132630262 ...