VCV002094308.5 - ClinVar

NM_001130987.2(DYSF):c.6173+1G>A

Germline

Classification

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

Likely pathogenic

2 out of 3 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.6173+1G>A

Variation ID: 2094308 Accession: VCV002094308.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.2 2: 71681111 (GRCh38) [ NCBI UCSC ] 2: 71908241 (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	Feb 8, 2023	Feb 25, 2025	Oct 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130987.2:c.6173+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_003494.4:c.6056+1G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001130455.2:c.6059+1G>A		splice donor
NM_001130976.2:c.6014+1G>A		splice donor
NM_001130977.2:c.6077+1G>A		splice donor
NM_001130978.2:c.6119+1G>A		splice donor
NM_001130979.2:c.6149+1G>A		splice donor
NM_001130980.2:c.6107+1G>A		splice donor
NM_001130981.2:c.6170+1G>A		splice donor
NM_001130982.2:c.6152+1G>A		splice donor
NM_001130983.2:c.6122+1G>A		splice donor
NM_001130984.2:c.6080+1G>A		splice donor
NM_001130985.2:c.6110+1G>A		splice donor
NM_001130986.2:c.6017+1G>A		splice donor
NC_000002.12:g.71681111G>A
NC_000002.11:g.71908241G>A
NG_008694.1:g.232489G>A
LRG_845:g.232489G>A
LRG_845t1:c.6056+1G>A
LRG_845t2:c.6173+1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:71681110:G:A

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: CA347226922 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	4227	4278

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.
Qualitative or quantitative defects of dysferlin	Likely pathogenic (1)	criteria provided, single submitter	Oct 23, 2023	RCV003021279.4
Miyoshi muscular dystrophy 1	Likely pathogenic (1)	criteria provided, single submitter	Sep 11, 2023	RCV003459695.1
Autosomal recessive limb-girdle muscular dystrophy type 2B	Likely pathogenic (1)	no assertion criteria provided	-	RCV004813212.1

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.
Likely pathogenic (Sep 11, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Miyoshi muscular dystrophy 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194212.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (Oct 23, 2023) C Contributing to aggregate classification	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: SCV003312280.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 16199547‚ 17698709‚ 20301480 Comment: This sequence change affects a donor splice site in intron 53 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 53 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 not present in population databases (gnomAD no frequency). 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: 2094308). 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)
Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2B Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Wuerzburg Accession: SCV005438219.1 First in ClinVar: Dec 22, 2024 Last updated: Dec 22, 2024	Number of individuals with the variant: 1

Comment:

This sequence change affects a donor splice site in intron 53 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 not present in population databases (gnomAD no frequency). 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: 2094308). 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.

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
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for this variant ...

Record last updated Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_001130987.2(DYSF):c.6173+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...