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.2844G>C (p.Trp948Cys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA233931

167021 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 56b257c4-0550-4d13-bef2-598c94fa5534

Approved on: 2025-03-06

Published on: 2025-04-04

HGVS expressions

NM_001130987.2:c.2844G>C

NM_001130987.2(DYSF):c.2844G>C (p.Trp948Cys)

NC_000002.12:g.71568318G>C

CM000664.2:g.71568318G>C

NC_000002.11:g.71795448G>C

CM000664.1:g.71795448G>C

NC_000002.10:g.71648956G>C

NG_008694.1:g.119696G>C

ENST00000698057.1:c.216G>C

ENST00000258104.8:c.2790G>C

ENST00000410020.8:c.2844G>C

ENST00000258104.7:c.2790G>C

ENST00000394120.6:c.2793G>C

ENST00000409366.5:c.2793G>C

ENST00000409582.7:c.2841G>C

ENST00000409651.5:c.2886G>C

ENST00000409744.5:c.2751G>C

ENST00000409762.5:c.2841G>C

ENST00000410020.7:c.2844G>C

ENST00000410041.1:c.2844G>C

ENST00000413539.6:c.2883G>C

ENST00000429174.6:c.2790G>C

NM_001130455.1:c.2793G>C

NM_001130976.1:c.2748G>C

NM_001130977.1:c.2748G>C

NM_001130978.1:c.2790G>C

NM_001130979.1:c.2883G>C

NM_001130980.1:c.2841G>C

NM_001130981.1:c.2841G>C

NM_001130982.1:c.2886G>C

NM_001130983.1:c.2793G>C

NM_001130984.1:c.2751G>C

NM_001130985.1:c.2844G>C

NM_001130986.1:c.2751G>C

NM_001130987.1:c.2844G>C

NM_003494.3:c.2790G>C

NM_001130455.2:c.2793G>C

NM_001130976.2:c.2748G>C

NM_001130977.2:c.2748G>C

NM_001130978.2:c.2790G>C

NM_001130979.2:c.2883G>C

NM_001130980.2:c.2841G>C

NM_001130981.2:c.2841G>C

NM_001130982.2:c.2886G>C

NM_001130983.2:c.2793G>C

NM_001130984.2:c.2751G>C

NM_001130985.2:c.2844G>C

NM_001130986.2:c.2751G>C

NM_003494.4:c.2790G>C

Pathogenic

PP4_Strong PP3 PM3 PM2_Supporting PS3_Moderate

Evidence Links 0

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.2790G>C variant in DYSF, which is also known as NM_001130987.2: c.2844G>C p.(Trp948Cys), is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 930, p.(Trp930Cys). This variant has been detected in at least three individuals with LGMD (PMID: 18853459, 36983702, 27602406), including confirmed in trans with a pathogenic variant (NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 18853459, LOVD Individual #00215573) and in unknown phase with a pathogenic variant (NM_003494.4: c.2643+1G>A, 0.5 pts, PMID: 36983702) (PM3). Although both patients were reported to have additional DYSF variants in unknown phase, these other variants could be classified as likely benign. At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 18853459). This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Trp930Cys 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 0.87, which is above 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; 03/06/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3.

PP4_Strong

At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 18853459).

PP3

The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). not in a splice region

PM3

This variant has been detected in at least three individuals with features of LGMD (PMID: 18853459, 36983702, 27602406), including confirmed in trans (c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 18853459; LOVD Individual #00215573) and in unknown phase (c.2643+1G>A, 0.5 pts, PMID: 36983702) with a pathogenic variant (PM3). Though both patients had additional DYSF variants in unknown phase, these can be classified as likely benign.

PM2_Supporting

This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting).

PS3_Moderate

Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Trp930Cys protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).

Curation History

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