VCV000550866.10 - ClinVar

NM_001130987.2(DYSF):c.4528-2A>G

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (3)

3 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001130987.2(DYSF):c.4528-2A>G

Variation ID: 550866 Accession: VCV000550866.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.2 2: 71643963 (GRCh38) [ NCBI UCSC ] 2: 71871093 (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	Aug 5, 2018	Feb 23, 2026	Oct 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130987.2:c.4528-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_003494.4:c.4411-2A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001130455.2:c.4414-2A>G		splice acceptor
NM_001130976.2:c.4369-2A>G		splice acceptor
NM_001130977.2:c.4432-2A>G		splice acceptor
NM_001130978.2:c.4474-2A>G		splice acceptor
NM_001130979.2:c.4504-2A>G		splice acceptor
NM_001130980.2:c.4462-2A>G		splice acceptor
NM_001130981.2:c.4525-2A>G		splice acceptor
NM_001130982.2:c.4507-2A>G		splice acceptor
NM_001130983.2:c.4477-2A>G		splice acceptor
NM_001130984.2:c.4435-2A>G		splice acceptor
NM_001130985.2:c.4465-2A>G		splice acceptor
NM_001130986.2:c.4372-2A>G		splice acceptor
NC_000002.12:g.71643963A>G
NC_000002.11:g.71871093A>G
NG_008694.1:g.195341A>G
LRG_845:g.195341A>G
LRG_845t1:c.4411-2A>G
LRG_845t2:c.4528-2A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:71643962:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA347217740 dbSNP: rs1213965862 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	4612	4666

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.
Autosomal recessive limb-girdle muscular dystrophy type 2B	Likely pathogenic (1)	no assertion criteria provided	Mar 13, 2017	RCV000665741.2
Neuromuscular disease caused by qualitative or quantitative defects of dysferlin	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 30, 2023	RCV001256195.6
not provided	Likely pathogenic (1)	criteria provided, single submitter	Feb 18, 2020	RCV001784234.5

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.	Expand all rows Collapse all rows 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 11, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dysferlinopathy (Autosomal recessive inheritance)	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics Accession: SCV001433002.1 First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020 Comment: found in compound with c.2423G>A	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Likely pathogenic (Feb 18, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV002024438.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 30, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004283978.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 16199547‚ 17698709‚ 20301480 Comment: show This sequence change affects an acceptor splice site in intron 40 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 550866). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Mar 13, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Autosomal recessive limb-girdle muscular dystrophy type 2B	Counsyl Accession: SCV000789909.2 First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025	Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

This sequence change affects an acceptor splice site in intron 40 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 550866). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dysferlinopathy.	Adam MP	-	2025	PMID: 20301480
Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes.	Nguyen K	Archives of neurology	2007	PMID: 17698709
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs1213965862 ...

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 Apr 13, 2026