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.5176T>C (p.Ser1726Pro)

CA347220902

665724 (ClinVar)

Gene: DYSF (HGNC:8291)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: a23be9e8-b9ae-44a9-a377-1c1f9e815b48

Approved on: 2025-01-28

Published on: 2025-03-07

HGVS expressions

NM_001130987.2:c.5176T>C

NM_001130987.2(DYSF):c.5176T>C (p.Ser1726Pro)

NC_000002.12:g.71665163T>C

CM000664.2:g.71665163T>C

NC_000002.11:g.71892293T>C

CM000664.1:g.71892293T>C

NC_000002.10:g.71745801T>C

NG_008694.1:g.216541T>C

ENST00000698057.1:c.2590T>C

ENST00000698058.1:c.1807T>C

ENST00000698059.1:c.1915T>C

ENST00000258104.8:c.5059T>C

ENST00000410020.8:c.5176T>C

ENST00000258104.7:c.5059T>C

ENST00000394120.6:c.5062T>C

ENST00000409366.5:c.5125T>C

ENST00000409582.7:c.5173T>C

ENST00000409651.5:c.5155T>C

ENST00000409744.5:c.5083T>C

ENST00000409762.5:c.5110T>C

ENST00000410020.7:c.5176T>C

ENST00000410041.1:c.5113T>C

ENST00000413539.6:c.5152T>C

ENST00000429174.6:c.5122T>C

ENST00000479049.6:n.1944T>C

NM_001130455.1:c.5062T>C

NM_001130976.1:c.5017T>C

NM_001130977.1:c.5080T>C

NM_001130978.1:c.5122T>C

NM_001130979.1:c.5152T>C

NM_001130980.1:c.5110T>C

NM_001130981.1:c.5173T>C

NM_001130982.1:c.5155T>C

NM_001130983.1:c.5125T>C

NM_001130984.1:c.5083T>C

NM_001130985.1:c.5113T>C

NM_001130986.1:c.5020T>C

NM_001130987.1:c.5176T>C

NM_003494.3:c.5059T>C

NM_001130455.2:c.5062T>C

NM_001130976.2:c.5017T>C

NM_001130977.2:c.5080T>C

NM_001130978.2:c.5122T>C

NM_001130979.2:c.5152T>C

NM_001130980.2:c.5110T>C

NM_001130981.2:c.5173T>C

NM_001130982.2:c.5155T>C

NM_001130983.2:c.5125T>C

NM_001130984.2:c.5083T>C

NM_001130985.2:c.5113T>C

NM_001130986.2:c.5020T>C

NM_003494.4:c.5059T>C

Likely Pathogenic

PM3 PP4_Strong PM2_Supporting PP3

PM5

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.5059T>C variant in DYSF, which is also known as NM_001130987.2: c.5176T>C p.(Ser1726Pro), is a missense variant predicted to cause substitution of serine by proline at amino acid 1687, p.(Ser1687Pro). This variant has been identified in one individual with a diagnosis of LGMD, where it it was confirmed in trans with a variant classified as pathogenic by the LGMD VCEP (c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3). This patient displayed progressive limb girdle muscle weakness and significantly reduced or absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.8, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely 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; 01/28/2025): PM3, PP4_Strong, PM2_Supporting, PP3.

PM3

This variant has been identified in trans with a pathogenic DYSF variant in an individual with LGMD (c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3). Confirmed in trans with complex allele containing c.2643+1G>A (approved and published as P without this observation) and c.4577A>C p.(Lys1526Thr) (approved and published as LB) No variants at this location in LOVD, no citations in ClinVar. 1 submission by Invitae/Labcorp as VUS in ClinVar, with no response to query.

PP4_Strong

At least one patient with this variant and a second DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). reported phenotype: moderate progressive muscle weakness with mild scapular winging and mild asymmetry predominantly in legs. muscle biopsy showed dystrophic features and inflammation. disease range dysferlin by blood monocyte assay. Absent dysferlin by IHC of muscle biopsy.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.8, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).

PM5

There are no other variants at this residue in ClinVar. No variants at this genomic position in LOVD.

Curation History

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