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>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA222120

94262 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2e9ec51a-a8fa-415e-a12f-e6732251b591

Approved on: 2025-04-17

Published on: 2025-05-16

HGVS expressions

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

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

NC_000002.12:g.71520905G>A

CM000664.2:g.71520905G>A

NC_000002.11:g.71748035G>A

CM000664.1:g.71748035G>A

NC_000002.10:g.71601543G>A

NG_008694.1:g.72283G>A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pathogenic

PM2_Supporting PVS1_Strong PM3_Supporting PP4_Strong

PS1

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>A variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>A, occurs within the canonical splice donor site of intron 11. RNAseq analysis has shown that this variant disrupts splicing, resulting in two different frameshifts and premature truncations, p.Arg313ProfsTer8 and p.His314GlufsTer9, as well as an inframe deletion of 66 amino acids, p.Val286_Pro351del (PMID: 36983702; PVS1_Strong_RNA). This variant has been identified in at least four individuals with LGMD (PMID: 27602406; 24488599; 36983702), including in unknown phase with a pathogenic variant (NM_003494.4: c.610C>T p.(Arg204Ter), 0.5 pts, PMID: 27602406; PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong). Another nucleotide change affecting the same splice motif, NM_003494.4: c.1053+5G>A, has also been shown to result in skipping of exon 11 and is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. The filtering allele frequency of this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1111878 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_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_Strong_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting.

PM2_Supporting

The filtering allele frequency of this variant is 0.000006973 (the upper threshold of the 95% CI of 3/1111878 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

PVS1_Strong

The NM_003494.4: c.1053+1G>A variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>A, occurs within the canonical splice donor site (+/- 1,2) of intron 11. RNAseq analysis has shown that this variant disrupts splicing, resulting in two different frameshifts and premature truncations, p.Arg313ProfsTer8 and p.His314GlufsTer9, as well as an inframe deletion of 66 amino acids, p.Val286_Pro351del (PMID: 36983702; PVS1_Strong_RNA).

PM3_Supporting

This variant has been identified in at least four individuals with LGMD (PMID: 27602406, 24488599, 36983702), including in unknown phase with a pathogenic variant (c.610C>T p.(Arg204Ter), 0.5 pts, PMID: 27602406; PM3_Supporting).

PP4_Strong

At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong).

PS1

Another nucleotide change affecting the same splice motif, NM_003494.4: c.1053+5G>A, has also been shown to result in skipping of exon 11 and is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. Opted not to apply given the c.1053+1G>A variant has two other splice consequences in addition to exon skipping. Applying this code would not change the variant classification.

Curation History

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