Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001130987.2(DYSF):c.953T>A (p.Val318Glu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA222220

94365 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 685c6f83-034e-4c37-9494-891f75306e44

Approved on: 2025-01-08

Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.953T>A

NM_001130987.2(DYSF):c.953T>A (p.Val318Glu)

NC_000002.12:g.71516990T>A

CM000664.2:g.71516990T>A

NC_000002.11:g.71744120T>A

CM000664.1:g.71744120T>A

NC_000002.10:g.71597628T>A

NG_008694.1:g.68368T>A

ENST00000258104.8:c.857T>A

ENST00000410020.8:c.953T>A

ENST00000258104.7:c.857T>A

ENST00000394120.6:c.860T>A

ENST00000409366.5:c.860T>A

ENST00000409582.7:c.950T>A

ENST00000409651.5:c.953T>A

ENST00000409744.5:c.860T>A

ENST00000409762.5:c.950T>A

ENST00000410020.7:c.953T>A

ENST00000410041.1:c.953T>A

ENST00000413539.6:c.950T>A

ENST00000429174.6:c.857T>A

NM_001130455.1:c.860T>A

NM_001130976.1:c.857T>A

NM_001130977.1:c.857T>A

NM_001130978.1:c.857T>A

NM_001130979.1:c.950T>A

NM_001130980.1:c.950T>A

NM_001130981.1:c.950T>A

NM_001130982.1:c.953T>A

NM_001130983.1:c.860T>A

NM_001130984.1:c.860T>A

NM_001130985.1:c.953T>A

NM_001130986.1:c.860T>A

NM_001130987.1:c.953T>A

NM_003494.3:c.857T>A

NM_001130455.2:c.860T>A

NM_001130976.2:c.857T>A

NM_001130977.2:c.857T>A

NM_001130978.2:c.857T>A

NM_001130979.2:c.950T>A

NM_001130980.2:c.950T>A

NM_001130981.2:c.950T>A

NM_001130982.2:c.953T>A

NM_001130983.2:c.860T>A

NM_001130984.2:c.860T>A

NM_001130985.2:c.953T>A

NM_001130986.2:c.860T>A

NM_003494.4:c.857T>A

Pathogenic

PM2_Supporting PM3_Strong PS3_Moderate PP3 PP4_Strong

PVS1 PS1 BP2 BP3 BP4 BP1 BP5 BP7 PP2 PM1 PM4 PM5 BA1 BS3 BS1

Evidence Links 1

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.857T>A variant in DYSF, which is also known as NM_001130987.2: c.953T>A p.(Val318Glu), is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 318 p.(Val318Glu). This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID: 18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID: 33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID: 18832576 (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID: 36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.95, which exceeds the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PM3_Strong, PP4_Strong, PS3_Moderate, PP3.

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the ClinGen LGMD threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM3_Strong

This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID: 18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID: 33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID: 18832576 (PM3_Strong).

PS3_Moderate

Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).

PP3

The computational predictor REVEL gives a score of 0.95, which exceeds the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).

PP4_Strong

At least one patient with this variant displayed progressive weakness and absent protein expression, which is highly specific for LGMD 2B (PP4_Strong, PMID: 18832576).

PVS1

RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID: 36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met).

PS1