Evidence Repository - Clinical Genome Resources

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Variant: NM_001130987.2(DYSF):c.1276+5G>A

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA1705673

289571 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 99807697-0026-407a-9fd6-32ba4873559f

Approved on: 2025-04-03

Published on: 2025-07-17

HGVS expressions

NM_001130987.2:c.1276+5G>A

NM_001130987.2(DYSF):c.1276+5G>A

NC_000002.12:g.71526351G>A

CM000664.2:g.71526351G>A

NC_000002.11:g.71753481G>A

CM000664.1:g.71753481G>A

NC_000002.10:g.71606989G>A

NG_008694.1:g.77729G>A

ENST00000258104.8:c.1180+5G>A

ENST00000410020.8:c.1276+5G>A

ENST00000258104.7:c.1180+5G>A

ENST00000394120.6:c.1183+5G>A

ENST00000409366.5:c.1183+5G>A

ENST00000409582.7:c.1273+5G>A

ENST00000409651.5:c.1276+5G>A

ENST00000409744.5:c.1183+5G>A

ENST00000409762.5:c.1273+5G>A

ENST00000410020.7:c.1276+5G>A

ENST00000410041.1:c.1276+5G>A

ENST00000413539.6:c.1273+5G>A

ENST00000429174.6:c.1180+5G>A

NM_001130455.1:c.1183+5G>A

NM_001130976.1:c.1180+5G>A

NM_001130977.1:c.1180+5G>A

NM_001130978.1:c.1180+5G>A

NM_001130979.1:c.1273+5G>A

NM_001130980.1:c.1273+5G>A

NM_001130981.1:c.1273+5G>A

NM_001130982.1:c.1276+5G>A

NM_001130983.1:c.1183+5G>A

NM_001130984.1:c.1183+5G>A

NM_001130985.1:c.1276+5G>A

NM_001130986.1:c.1183+5G>A

NM_001130987.1:c.1276+5G>A

NM_003494.3:c.1180+5G>A

NM_001130455.2:c.1183+5G>A

NM_001130976.2:c.1180+5G>A

NM_001130977.2:c.1180+5G>A

NM_001130978.2:c.1180+5G>A

NM_001130979.2:c.1273+5G>A

NM_001130980.2:c.1273+5G>A

NM_001130981.2:c.1273+5G>A

NM_001130982.2:c.1276+5G>A

NM_001130983.2:c.1183+5G>A

NM_001130984.2:c.1183+5G>A

NM_001130985.2:c.1276+5G>A

NM_001130986.2:c.1183+5G>A

NM_003494.4:c.1180+5G>A

Pathogenic

PVS1 PM3 PM2_Supporting PP4_Strong

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.1180+5G>A variant in DYSF, which is also known as NM_001130987.2: c.1276+5G>A, occurs within the splice donor region of intron 12 and has a SpliceAI score of 0.87 for donor loss and 0.44 for gain of an alternative donor. RNAseq analysis has demonstrated abnormal splicing due to this variant, which resulted in either an insertion of 28bp or a deletion of 28bp. Both events led to a frameshift and premature truncation: p.(Met394SerfsTer27) and p.(Val385TrpfsTer5) (PMID: 36983702; PVS1_RNA). This variant has been reported in at least nine individuals with dysferlinopathy (PMID: 18853459, 25574751, 27647186, 28403181, 32400077, 36983702), including in unknown phase with a pathogenic variant in at least two patients (c.3112C>T p.(Arg1038Ter), 0.5 pts, PMID: 36983702; c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID: 25574751) and in a homozygous state in one individual (0.5 pts, PMID: 27647186, 28403181) (PM3). At least one patient with this variant displayed progressive muscle weakness and reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 18853459, 25574751, 28403181, 36983702; PP4_Strong). The filtering allele frequency of this variant is 0.000028265 (the upper threshold of the 95% CI of 22/1111436 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, 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; 04/03/2025): PVS1_RNA, PM3, PP4_Strong, PM2_Supporting.

PVS1

The NM_003494.4: c.1180+5G>A variant in DYSF, which is also known as NM_001130987.2: c.1276+5G>A, occurs within the splice acceptor region of intron 12 and has a SpliceAI score of 0.87 for donor loss and 0.44 for gain of an alternative donor. RNAseq analysis has demonstrated abnormal splicing due to this variant, which resulted in either an insertion of 28bp or a deletion of 28bp. Both events led to a frameshift and premature truncation: p.(Met394SerfsTer27) and p.(Val385TrpfsTer5) (PMID: 36983702; PVS1_RNA).

PM3

This variant has been reported in at least nine individuals with dysferlinopathy (PMID: 18853459, 25574751, 27647186, 28403181, 32400077, 36983702), including in unknown phase with a pathogenic variant in at least two patients (c.3112C>T p.(Arg1038Ter), 0.5 pts, PMID: 36983702; c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID: 25574751) and in a homozygous state in one individual (0.5 pts, PMID: 27647186, 28403181) (PM3). c.3112C>T p.(Arg1038Ter) and c.6124C>T p.(Arg2042Cys) are both predicted on a different haplotype than c.1180+5G>A for European (non-Finnish) population, no prediction for other groups

PM2_Supporting

The filtering allele frequency of this variant is 0.000028265 (the upper threshold of the 95% CI of 22/1111436 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

PP4_Strong

At least one patient with this variant displayed progressive muscle weakness and reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 18853459, 25574751, 28403181, 36983702; PP4_Strong).

Curation History

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