Variant: NM_001130987.2(DYSF):c.2697+1G>C

CA347214076

936623 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 970a046b-de7a-44c4-ac0d-b357c11f10b6

Approved on: 2025-01-08

Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.2697+1G>C
NM_001130987.2(DYSF):c.2697+1G>C
NC_000002.12:g.71568083G>C
CM000664.2:g.71568083G>C
NC_000002.11:g.71795213G>C
CM000664.1:g.71795213G>C
NC_000002.10:g.71648721G>C
NG_008694.1:g.119461G>C
ENST00000698057.1:c.69+1G>C
ENST00000258104.8:c.2643+1G>C
ENST00000410020.8:c.2697+1G>C
ENST00000258104.7:c.2643+1G>C
ENST00000394120.6:c.2646+1G>C
ENST00000409366.5:c.2646+1G>C
ENST00000409582.7:c.2694+1G>C
ENST00000409651.5:c.2739+1G>C
ENST00000409744.5:c.2604+1G>C
ENST00000409762.5:c.2694+1G>C
ENST00000410020.7:c.2697+1G>C
ENST00000410041.1:c.2697+1G>C
ENST00000413539.6:c.2736+1G>C
ENST00000429174.6:c.2643+1G>C
NM_001130455.1:c.2646+1G>C
NM_001130976.1:c.2601+1G>C
NM_001130977.1:c.2601+1G>C
NM_001130978.1:c.2643+1G>C
NM_001130979.1:c.2736+1G>C
NM_001130980.1:c.2694+1G>C
NM_001130981.1:c.2694+1G>C
NM_001130982.1:c.2739+1G>C
NM_001130983.1:c.2646+1G>C
NM_001130984.1:c.2604+1G>C
NM_001130985.1:c.2697+1G>C
NM_001130986.1:c.2604+1G>C
NM_001130987.1:c.2697+1G>C
NM_003494.3:c.2643+1G>C
NM_001130455.2:c.2646+1G>C
NM_001130976.2:c.2601+1G>C
NM_001130977.2:c.2601+1G>C
NM_001130978.2:c.2643+1G>C
NM_001130979.2:c.2736+1G>C
NM_001130980.2:c.2694+1G>C
NM_001130981.2:c.2694+1G>C
NM_001130982.2:c.2739+1G>C
NM_001130983.2:c.2646+1G>C
NM_001130984.2:c.2604+1G>C
NM_001130985.2:c.2697+1G>C
NM_001130986.2:c.2604+1G>C
NM_003494.4:c.2643+1G>C

Pathogenic

• Met criteria codes: PP1 PM2 PM3 PP4_Strong PVS1_Moderate

• Not Met criteria codes: PS1

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

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.2643+1G>C variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>C, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids (PVS1_Moderate). This variant has been confirmed in trans with a likely pathogenic variant in an individual with a clinical diagnosis of LGMD (c.4194C>A p.(Cys1398Ter), 1.0 pt, PMID: 21522182) (PM3). This patient also showed absent dysferlin expression, which is highly specific for DYSF-related LGMD (PP4_Strong). The variant was reported to co-segregate with the disease in one affected family member (PP1). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. 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; 01/08/2025): PVS1_Moderate, PM3, PP4_Strong, PP1, PM2_Supporting.

Met criteria codes

• PP1: The variant was also reported to co-segregate with the disease in one affected family member (PP1; PMID: 21522182).
• PM2: This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).
• PM3: This variant has been confirmed in trans with a likely pathogenic variant in an individual with LGMD (c.4194C>A p.(Cys1398Ter), 1.0 pt, PMID: 21522182).
• PP4_Strong: At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression, which is specific for DYSF-related LGMD (PP4_Strong; PMID: 21522182).
• PVS1_Moderate: The NM_003494.4: c.2643+1G>C variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>C, occurs within the canonical splice donor site (+/- 1,2) of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids (PVS1_Moderate).

Not Met criteria codes

• PS1: Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. PS1 was applied to the c.2643+1G>A variant.