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.1149+1G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA347212236

808764 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 35a5ea05-7629-44a2-b03d-05361567af13

Approved on: 2025-04-17

Published on: 2025-05-16

HGVS expressions

NM_001130987.2:c.1149+1G>C

NM_001130987.2(DYSF):c.1149+1G>C

NC_000002.12:g.71520905G>C

CM000664.2:g.71520905G>C

NC_000002.11:g.71748035G>C

CM000664.1:g.71748035G>C

NC_000002.10:g.71601543G>C

NG_008694.1:g.72283G>C

ENST00000258104.8:c.1053+1G>C

ENST00000410020.8:c.1149+1G>C

ENST00000258104.7:c.1053+1G>C

ENST00000394120.6:c.1056+1G>C

ENST00000409366.5:c.1056+1G>C

ENST00000409582.7:c.1146+1G>C

ENST00000409651.5:c.1149+1G>C

ENST00000409744.5:c.1056+1G>C

ENST00000409762.5:c.1146+1G>C

ENST00000410020.7:c.1149+1G>C

ENST00000410041.1:c.1149+1G>C

ENST00000413539.6:c.1146+1G>C

ENST00000429174.6:c.1053+1G>C

NM_001130455.1:c.1056+1G>C

NM_001130976.1:c.1053+1G>C

NM_001130977.1:c.1053+1G>C

NM_001130978.1:c.1053+1G>C

NM_001130979.1:c.1146+1G>C

NM_001130980.1:c.1146+1G>C

NM_001130981.1:c.1146+1G>C

NM_001130982.1:c.1149+1G>C

NM_001130983.1:c.1056+1G>C

NM_001130984.1:c.1056+1G>C

NM_001130985.1:c.1149+1G>C

NM_001130986.1:c.1056+1G>C

NM_001130987.1:c.1149+1G>C

NM_003494.3:c.1053+1G>C

NM_001130455.2:c.1056+1G>C

NM_001130976.2:c.1053+1G>C

NM_001130977.2:c.1053+1G>C

NM_001130978.2:c.1053+1G>C

NM_001130979.2:c.1146+1G>C

NM_001130980.2:c.1146+1G>C

NM_001130981.2:c.1146+1G>C

NM_001130982.2:c.1149+1G>C

NM_001130983.2:c.1056+1G>C

NM_001130984.2:c.1056+1G>C

NM_001130985.2:c.1149+1G>C

NM_001130986.2:c.1056+1G>C

NM_003494.4:c.1053+1G>C

Pathogenic

PP4_Strong PS1_Supporting PM2_Supporting PVS1

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 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.1053+1G>C variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>C, occurs within the canonical splice donor site of intron 11 and is predicted to cause skipping of biologically relevant exon 11/55, resulting in a frameshift and premature truncation leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in one individual with features of LGMD, where it was observed in unknown phase with a likely pathogenic DYSF variant (NM_003494.4: c.4024C>T p.(Arg1342Trp), 0.25 pts, Jain Foundation Dysferlin Registry internal data communication) (PM3_Supporting not met). This patient had a clinical suspicion of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Another nucleotide change affecting the same splice donor dinucleotide position and with the same predicted splice effect, NM_003494.4: c.1053+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Supporting). 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; 04/17/2025): PVS1, PP4_Strong, PM2_Supporting, PS1_Supporting.

PP4_Strong

At least one patient with this variant and second presumed diagnostic variant in DYSF had a clinical suspicion of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; Jain Foundation Dysferlin Registry internal data communication).

PS1_Supporting

Another nucleotide change affecting the same splice donor ±1,2 dinucleotide position and with the same predicted splice effect, NM_003494.4: c.1053+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Supporting).

PM2_Supporting

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

PVS1

The NM_003494.4: c.1053+1G>C variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>C, occurs within the canonical splice donor site (+/- 1,2) of intron 11 and is predicted to cause skipping of biologically relevant exon 11/55, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).

PM3

This variant has been identified in one individual with features of LGMD, where it was observed in unknown phase with a likely pathogenic DYSF variant (c.4024C>T p.(Arg1342Trp), 0.25 pts, Jain Foundation Dysferlin Registry internal data communication) (criterion not met).

Curation History

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