VCV002674961.3 - ClinVar

NM_001130987.2(DYSF):c.959dup (p.Asp320fs)

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.

(3)

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_001130987.2(DYSF):c.959dup (p.Asp320fs)

Variation ID: 2674961 Accession: VCV002674961.3

Type and length

Duplication, 1 bp

Location

Cytogenetic: 2p13.2 2: 71516995-71516996 (GRCh38) [ NCBI UCSC ] 2: 71744125-71744126 (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	Dec 30, 2023	Jun 17, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130987.2:c.959dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001124459.1:p.Asp320fs	frameshift
NM_003494.4:c.863dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003485.1:p.Asp288fs	frameshift
NM_001130455.2:c.866dup	NP_001123927.1:p.Asp289fs	frameshift
NM_001130976.2:c.863dup	NP_001124448.1:p.Asp288fs	frameshift
NM_001130977.2:c.863dup	NP_001124449.1:p.Asp288fs	frameshift
NM_001130978.2:c.863dup	NP_001124450.1:p.Asp288fs	frameshift
NM_001130979.2:c.956dup	NP_001124451.1:p.Asp319fs	frameshift
NM_001130980.2:c.956dup	NP_001124452.1:p.Asp319fs	frameshift
NM_001130981.2:c.956dup	NP_001124453.1:p.Asp319fs	frameshift
NM_001130982.2:c.959dup	NP_001124454.1:p.Asp320fs	frameshift
NM_001130983.2:c.866dup	NP_001124455.1:p.Asp289fs	frameshift
NM_001130984.2:c.866dup	NP_001124456.1:p.Asp289fs	frameshift
NM_001130985.2:c.959dup	NP_001124457.1:p.Asp320fs	frameshift
NM_001130986.2:c.866dup	NP_001124458.1:p.Asp289fs	frameshift
NC_000002.12:g.71516996dup
NC_000002.11:g.71744126dup
NG_008694.1:g.68374dup
LRG_845:g.68374dup
LRG_845t1:c.863dup	LRG_845p1:p.Asp288fs
LRG_845t2:c.959dup	LRG_845p2:p.Asp320fs

... more HGVS ... less HGVS

Protein change

D288fs, D289fs, D319fs, D320fs

Other names

Canonical SPDI

NC_000002.12:71516995:A:AA

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

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.
DYSF		-	-	GRCh38 GRCh37	4065	4114

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.
Miyoshi muscular dystrophy 1	Likely pathogenic (1)	criteria provided, single submitter	Nov 9, 2023	RCV003467865.2
Qualitative or quantitative defects of dysferlin	Pathogenic (1)	criteria provided, single submitter	Mar 26, 2023	RCV003575100.2
Autosomal recessive limb-girdle muscular dystrophy type 2B	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2024	RCV004574033.1

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 (Mar 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Qualitative or quantitative defects of dysferlin Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004292550.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 14673575‚ 33610434‚ 33715265‚ 17698709‚ 20301480 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 14673575, … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 14673575, 33610434, 33715265). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp288Glufs*40) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). (less)
Likely pathogenic (Nov 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Miyoshi muscular dystrophy 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194193.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Autosomal recessive limb-girdle muscular dystrophy type 2B Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051757.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 14673575, 33610434, 33715265). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp288Glufs*40) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480).

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
Deep phenotyping of an international series of patients with late-onset dysferlinopathy.	Fernández-Eulate G	European journal of neurology	2021	PMID: 33715265
Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease.	Moore U	Neuromuscular disorders : NMD	2021	PMID: 33610434
Dysferlinopathy.	Adam MP	-	2021	PMID: 20301480
Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes.	Nguyen K	Archives of neurology	2007	PMID: 17698709
Variable reduction of caveolin-3 in patients with LGMD2B/MM.	Walter MC	Journal of neurology	2003	PMID: 14673575

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001130987.2(DYSF):c.959dup (p.Asp320fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...