Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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

CA222141

94291 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f62f2ccc-f972-4206-91e8-dcfee3ed434a
Approved on: 2025-01-08
Published on: 2025-01-08

HGVS expressions

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

Met criteria codes 4
PP4_Strong PVS1_Moderate PM3_Strong PS1
Not Met criteria codes 1
BS1

Evidence Links 0

Expert Panel

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.2643+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>A, 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. Skipping of exon 25 was confirmed by minigene assay and RNAseq (PMID 25312915, 36983702; PVS1_Moderate_RNA). This variant has been detected in at least eight unrelated individuals with LGMD (PMID: 30564623, 36983702, 33927379, 23243261, 22246893, 18853459). Of these individuals, four were homozygous (1.0 pt), and four were compound heterozygous; in at least two cases, the variant was confirmed in trans with a pathogenic or likely pathogenic variant (c.1948delC p.(Leu650TyrfsTer6), 1.0 pt; c.4497delT p.(Phe1499LeufsTer4), 1.0 pt) (PM3_Strong). At least one of these patients displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 33927379). The filtering allele frequency for this variant is 0.001335 in gnomAD v2.1.1 African/African American genomes (the lower threshold of the 95% CI of 18/8708), which is higher than the LGMD VCEP threshold of 0.001 for BS1; however, this variant is a frequently observed variant among patients, and the VCEP opted not to apply this code (BS1 exception). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the threshold for the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. Although the population frequency of this variant provides benign evidence, the VCEP considers this not inconsistent with the final classification given the frequency at which it is observed in the patient population. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate_RNA, PS1, PM3_Strong, PP4_Strong.
Met criteria codes
PP4_Strong
At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and/or blood monocytes, which is specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 33927379).
PVS1_Moderate
The NM_003494.4: c.2643+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>A, 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. Skipping of exon 25 was confirmed by minigene assay and RNAseq (PMID 25312915, 36983702; PVS1_Moderate_RNA).
PM3_Strong
This variant has been detected in at least 8 unrelated individuals with LGMD (PMID: 30564623, 36983702, 33927379, 23243261, 22246893, 18853459). Of these individuals, four were homozygous (1.0 pts), and four were compound heterozygous; in at least two cases, the variant was confirmed in trans with a pathogenic or likely pathogenic variant (c.1948delC p.(Leu650TyrfsTer6), 1.0 pt; c.4497delT p.(Phe1499LeufsTer4), 1.0 pt). (PM3_Strong)
PS1
Another nucleotide change affecting the same splice region and with the same predicted splice effect, NM_003494.4: c.2643+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1).
Not Met criteria codes
BS1
The filtering allele frequency for this variant is 0.001335 in gnomAD v2.1.1 African/African American genomes (the lower threshold of the 95% CI of 18/8708), which is higher than the LGMD VCEP threshold of 0.001; however, this variant is a frequently observed variant among patients, and the VCEP opted not to apply this code (BS1 exception).
Curation History
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