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.5635G>A (p.Val1879Met)

CA10604806

284471 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: 3bab5f18-d034-477e-a0f9-4537463e90bf

Approved on: 2026-01-23

Published on: 2026-02-17

HGVS expressions

NM_001130987.2(DYSF):c.5635G>A (p.Val1879Met)

NM_001130987.2:c.5635G>A

NC_000002.12:g.71669200G>A

CM000664.2:g.71669200G>A

NC_000002.11:g.71896330G>A

CM000664.1:g.71896330G>A

NC_000002.10:g.71749838G>A

NG_008694.1:g.220578G>A

ENST00000698057.1:c.3049G>A

ENST00000698058.1:c.2266G>A

ENST00000698059.1:c.2374G>A

ENST00000258104.8:c.5518G>A

ENST00000410020.8:c.5635G>A

ENST00000258104.7:c.5518G>A

ENST00000394120.6:c.5521G>A

ENST00000409366.5:c.5584G>A

ENST00000409582.7:c.5632G>A

ENST00000409651.5:c.5614G>A

ENST00000409744.5:c.5542G>A

ENST00000409762.5:c.5569G>A

ENST00000410020.7:c.5635G>A

ENST00000410041.1:c.5572G>A

ENST00000413539.6:c.5611G>A

ENST00000429174.6:c.5581G>A

ENST00000479049.6:n.2403G>A

NM_001130455.1:c.5521G>A

NM_001130976.1:c.5476G>A

NM_001130977.1:c.5539G>A

NM_001130978.1:c.5581G>A

NM_001130979.1:c.5611G>A

NM_001130980.1:c.5569G>A

NM_001130981.1:c.5632G>A

NM_001130982.1:c.5614G>A

NM_001130983.1:c.5584G>A

NM_001130984.1:c.5542G>A

NM_001130985.1:c.5572G>A

NM_001130986.1:c.5479G>A

NM_001130987.1:c.5635G>A

NM_003494.3:c.5518G>A

NM_001130455.2:c.5521G>A

NM_001130976.2:c.5476G>A

NM_001130977.2:c.5539G>A

NM_001130978.2:c.5581G>A

NM_001130979.2:c.5611G>A

NM_001130980.2:c.5569G>A

NM_001130981.2:c.5632G>A

NM_001130982.2:c.5614G>A

NM_001130983.2:c.5584G>A

NM_001130984.2:c.5542G>A

NM_001130985.2:c.5572G>A

NM_001130986.2:c.5479G>A

NM_003494.4:c.5518G>A

Pathogenic

PS3_Moderate PP3 PM3 PP4_Strong PM2_Supporting

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.5518G>A variant in DYSF, which is also known as NM_001130987.2: c.5635G>A p.(Val1879Met), is a missense variant predicted to cause substitution of valine to methionine at amino acid 1840, p.(Val1840Met). This variant has been observed in at least three individuals with LGMD, including two with a second pathogenic variant in unknown phase (NM_003494.4: c.5077C>T p.(Arg1693Trp), 0.5 pts, PMID: 30564623, LOVD Individual #00220833; c.1397+2dup, 0.5 pts, Jain Foundation Dysferlin Registry, internal data communication) (PM3). At least one of these individuals also had absent dysferlin expression in muscle, which is highly specific for DYSF-related LGMD (Jain Foundation Dysferlin Registry, internal data communication; PP4_Strong). The highest population frequency of this variant in gnomAD v4.1.0 is 0.00002247 in the South Asian population (2/89002 chromosomes), which is less than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Val1840Met 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 0.82, which is above the LGMD VCEP threshold of ≥0.70 (PP3). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 01/23/2026): PP4_Strong, PS3_Moderate, PM2_Supporting, PM3, PP3.

PS3_Moderate

Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Val1840Met 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 0.82, which is above the LGMD VCEP threshold of ≥0.70 (PP3). Splice AI: 0.01

PM3

This variant has been observed in at least three individuals with LGMD, including two with a second pathogenic variant in unknown phase (c.5077C>T p.(Arg1693Trp), 0.5 pts, PMID: 30564623, LOVD Individual #00220833; c.1397+2dup, 0.5 pts, Jain Foundation Dysferlin Registry, internal data communication) (PM3).

PP4_Strong

At least one individual with two presumed diagnostic variants also had absent dysferlin expression in muscle, which is highly specific for DYSF-related LGMD (Jain Foundation Dysferlin Registry, internal data communication; PP4_Strong).

PM2_Supporting

The highest population frequency of this variant in gnomAD v4.1.0 is 0.00002247 in the South Asian population (2/89002 chromosomes), which is less than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting).

Curation History

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