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.5149T>C (p.Cys1717Arg)

CA347220599

2674972 (ClinVar)

Gene: DYSF (HGNC:8291)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 43b2838d-0637-4aac-a04f-99c529f22fcd

Approved on: 2026-01-23

Published on: 2026-02-17

HGVS expressions

NM_001130987.2(DYSF):c.5149T>C (p.Cys1717Arg)

NM_001130987.2:c.5149T>C

NC_000002.12:g.71664413T>C

CM000664.2:g.71664413T>C

NC_000002.11:g.71891543T>C

CM000664.1:g.71891543T>C

NC_000002.10:g.71745051T>C

NG_008694.1:g.215791T>C

ENST00000698057.1:c.2563T>C

ENST00000698058.1:c.1780T>C

ENST00000698059.1:c.1888T>C

ENST00000258104.8:c.5032T>C

ENST00000410020.8:c.5149T>C

ENST00000258104.7:c.5032T>C

ENST00000394120.6:c.5035T>C

ENST00000409366.5:c.5098T>C

ENST00000409582.7:c.5146T>C

ENST00000409651.5:c.5128T>C

ENST00000409744.5:c.5056T>C

ENST00000409762.5:c.5083T>C

ENST00000410020.7:c.5149T>C

ENST00000410041.1:c.5086T>C

ENST00000413539.6:c.5125T>C

ENST00000429174.6:c.5095T>C

ENST00000479049.6:n.1917T>C

NM_001130455.1:c.5035T>C

NM_001130976.1:c.4990T>C

NM_001130977.1:c.5053T>C

NM_001130978.1:c.5095T>C

NM_001130979.1:c.5125T>C

NM_001130980.1:c.5083T>C

NM_001130981.1:c.5146T>C

NM_001130982.1:c.5128T>C

NM_001130983.1:c.5098T>C

NM_001130984.1:c.5056T>C

NM_001130985.1:c.5086T>C

NM_001130986.1:c.4993T>C

NM_001130987.1:c.5149T>C

NM_003494.3:c.5032T>C

NM_001130455.2:c.5035T>C

NM_001130976.2:c.4990T>C

NM_001130977.2:c.5053T>C

NM_001130978.2:c.5095T>C

NM_001130979.2:c.5125T>C

NM_001130980.2:c.5083T>C

NM_001130981.2:c.5146T>C

NM_001130982.2:c.5128T>C

NM_001130983.2:c.5098T>C

NM_001130984.2:c.5056T>C

NM_001130985.2:c.5086T>C

NM_001130986.2:c.4993T>C

NM_003494.4:c.5032T>C

Pathogenic

PM2_Supporting PP3 PM5 PP4_Strong PS3_Moderate

PM3

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.5032T>C variant in DYSF, which is also known as NM_001130987.2: c.5149T>C p.(Cys1717Arg), is a missense variant predicted to cause substitution of cysteine to arginine at amino acid 1678, p.(Cys1678Arg). This variant has been observed in one individual with LGMD with a second variant in unknown phase. This individual also had absent dysferlin expression in muscle, which is highly specific for DYSF-related LGMD (PMID: 25591676; PP4_Strong). The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001098 in the South Asian population (1/91088 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 Cys1678Arg 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 is above the LGMD VCEP threshold of ≥0.70 (PP3). In addition, two other missense variants at the same codon, NM_003494.4: c.5033G>A p.(Cys1678Tyr) and c.5033G>C p.(Cys1678Ser), have been classified as at least likely pathogenic by the ClinGen LGMD VCEP (PM5). 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, PM5, PP3.

PM2_Supporting

The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001098 in the South Asian population (1/91088 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.95, which is above the LGMD VCEP threshold of ≥0.70 (PP3). Splice AI: 0.14

PM5

Two other missense variants at the same codon, c.5033G>A p.(Cys1678Tyr) and c.5033G>C p.(Cys1678Ser), have been classified as at least likely pathogenic by the ClinGen LGMD VCEP (PM5). Both are LP without PM5 application. Splice AI<0.5 for all variants

PP4_Strong

Individual with clinical features of LGMD and two presumably diagnostic variants had absent dysferlin expression in muscle, which is highly specific for DYSF-related LGMD (PMID: 25591676; PP4_Strong).

PS3_Moderate

Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Cys1678Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).

PM3

This variant has been observed in one individual with LGMD with a second variant in unknown phase (PMID: 25591676).

Curation History

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