VCV000289486.16 - ClinVar

NM_000117.3(EMD):c.251_255del (p.Leu84fs)

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.251_255del (p.Leu84fs)

Variation ID: 289486 Accession: VCV000289486.16

Type and length

Deletion, 5 bp

Location

Cytogenetic: Xq28 X: 154380002-154380006 (GRCh38) [ NCBI UCSC ] X: 153608362-153608366 (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	Apr 4, 2013	Feb 14, 2024	Aug 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000117.3:c.251_255del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000108.1:p.Leu84fs	frameshift
NM_000117.2:c.251_255del5
NM_000117.2:c.251_255delTCTAC
NC_000023.11:g.154380005_154380009del
NC_000023.10:g.153608365_153608369del
NG_008677.1:g.10570_10574del
LRG_745:g.10570_10574del
LRG_745t1:c.251_255del	LRG_745p1:p.Leu84fs

... more HGVS ... less HGVS

Protein change

L84fs

Other names

Canonical SPDI

NC_000023.11:154380001:TACTCTAC:TAC

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: CA10561551 LOVD 3: EMD_000023 OMIM: 300384.0010 dbSNP: rs782452523 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	541	808

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 25, 2016	RCV000498396.6
X-linked Emery-Dreifuss muscular dystrophy	Pathogenic (2)	criteria provided, single submitter	Aug 25, 2023	RCV001216679.11
EMD-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 25, 2023	RCV003401269.4
Emery-Dreifuss muscular dystrophy 1, X-linked	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2022	RCV003492030.2

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 (Jul 25, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes, no Allele origin: maternal, unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000590855.1 First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017	Publications: PubMed (1) PubMed: 9536090 Observation 1: Age: 10-19 years Sex: male Observation 2: Age: 20-29 years Sex: female Observation 3: Age: 40-49 years Sex: female
Pathogenic (Jul 25, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000701354.2 First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017	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 (ACMG Guidelines, 2015) Method: clinical testing	EMD-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120544.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The EMD c.251_255del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu84Profs7). This variant has been reported in individuals with Emery-Dreifuss … (more) The EMD c.251_255del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu84Profs7). This variant has been reported in individuals with Emery-Dreifuss muscular dystrophy (Reported as delTCTAC in Manilal et al 1998. PubMed ID: 9536090; Dai X et al 2019. PubMed ID: 31645980). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in EMD are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Mar 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Emery-Dreifuss muscular dystrophy 1, X-linked Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003821371.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 25, 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: SCV001388488.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 24365856‚ 9536090‚ 10382910‚ 21697856‚ 24375709‚ 25210889‚ 31645980 Comment: This sequence change creates a premature translational stop signal (p.Leu84Profs7) 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.Leu84Profs7) 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: 9536090, 10382910, 21697856, 24375709, 25210889, 31645980). ClinVar contains an entry for this variant (Variation ID: 289486). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 1998)	no assertion criteria provided Method: literature only	EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032163.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 9536090 Comment on evidence: In 2 brothers with Emery-Dreifuss muscular dystrophy (310300), Manilal et al. (1998) identified a 5-bp deletion (TCTAC) spanning nucleotides 631-635 of the EMD gene.

Comment:

The EMD c.251_255del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu84Profs*7). This variant has been reported in individuals with Emery-Dreifuss muscular dystrophy (Reported as delTCTAC in Manilal et al 1998. PubMed ID: 9536090; Dai X et al 2019. PubMed ID: 31645980). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in EMD are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu84Profs*7) 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: 9536090, 10382910, 21697856, 24375709, 25210889, 31645980). ClinVar contains an entry for this variant (Variation ID: 289486). For these reasons, this variant has been classified as Pathogenic.

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
Targeted next-generation sequencing identified a known EMD mutation in a Chinese patient with Emery-Dreifuss muscular dystrophy.	Dai X	Human genome variation	2019	PMID: 31645980
Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.	Meinke P	PLoS genetics	2014	PMID: 25210889
Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies.	Li P	Human mutation	2014	PMID: 24375709
Emerin in health and disease.	Koch AJ	Seminars in cell & developmental biology	2014	PMID: 24365856
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
Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy.	Hoeltzenbein M	Neuromuscular disorders : NMD	1999	PMID: 10382910
Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression.	Manilal S	Human molecular genetics	1998	PMID: 9536090
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EMD	-	-	-	-

Text-mined citations for rs782452523 ...

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.251_255del (p.Leu84fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs782452523 ...