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 label mismatch: DYSF vs undefined
  • 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.4873C>T (p.Arg1625Ter)

CA222174

94330 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7c197707-5386-4dad-acb3-5912cd701658
Approved on: 2025-04-16
Published on: 2025-05-16

HGVS expressions

NM_001130987.2:c.4873C>T
NM_001130987.2(DYSF):c.4873C>T (p.Arg1625Ter)
NC_000002.12:g.71658995C>T
CM000664.2:g.71658995C>T
NC_000002.11:g.71886125C>T
CM000664.1:g.71886125C>T
NC_000002.10:g.71739633C>T
NG_008694.1:g.210373C>T
ENST00000698057.1:c.2287C>T
ENST00000698058.1:c.1504C>T
ENST00000698059.1:c.1612C>T
ENST00000258104.8:c.4756C>T
ENST00000410020.8:c.4873C>T
ENST00000258104.7:c.4756C>T
ENST00000394120.6:c.4759C>T
ENST00000409366.5:c.4822C>T
ENST00000409582.7:c.4870C>T
ENST00000409651.5:c.4852C>T
ENST00000409744.5:c.4780C>T
ENST00000409762.5:c.4807C>T
ENST00000410020.7:c.4873C>T
ENST00000410041.1:c.4810C>T
ENST00000413539.6:c.4849C>T
ENST00000429174.6:c.4819C>T
ENST00000479049.6:n.1641C>T
NM_001130455.1:c.4759C>T
NM_001130976.1:c.4714C>T
NM_001130977.1:c.4777C>T
NM_001130978.1:c.4819C>T
NM_001130979.1:c.4849C>T
NM_001130980.1:c.4807C>T
NM_001130981.1:c.4870C>T
NM_001130982.1:c.4852C>T
NM_001130983.1:c.4822C>T
NM_001130984.1:c.4780C>T
NM_001130985.1:c.4810C>T
NM_001130986.1:c.4717C>T
NM_001130987.1:c.4873C>T
NM_003494.3:c.4756C>T
NM_001130455.2:c.4759C>T
NM_001130976.2:c.4714C>T
NM_001130977.2:c.4777C>T
NM_001130978.2:c.4819C>T
NM_001130979.2:c.4849C>T
NM_001130980.2:c.4807C>T
NM_001130981.2:c.4870C>T
NM_001130982.2:c.4852C>T
NM_001130983.2:c.4822C>T
NM_001130984.2:c.4780C>T
NM_001130985.2:c.4810C>T
NM_001130986.2:c.4717C>T
NM_003494.4:c.4756C>T
More

Pathogenic

Met criteria codes 3
PP4_Strong PM3_Strong PVS1
Not Met criteria codes 1
PM2

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.4756C>T p.(Arg1586Ter) variant in DYSF, which is also known as NM_001130987.2: c.4873C>T p.(Arg1625Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 43/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least five patients with features consistent with LGMD (PMID: 36983702; 23641709; 23530687; 11468312), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 11468312) and in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.265C>T p.(Arg89Ter), 1.0 pt, PMID: 23641709; NM_003494.4: c.3113G>C p.(Arg1038Pro), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702; 33610434). The filtering allele frequency of this variant is 0.0001061 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 4/86258 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). 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; 04/16/2025): PVS1, PM3_Strong, PP4_Strong.
Met criteria codes
PP4_Strong
At least one patient with this variant and a second presumed diagnostic variant in DYSF had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 33610434).
PM3_Strong
This variant has been reported in at least five patients with features consistent with LGMD (PMID: 36983702, 23641709, 23530687, 11468312), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 11468312) and in trans with a likely pathogenic or pathogenic variant in two individuals (c.265C>T p.(Arg89Ter), 1.0 pt, PMID: 23641709; c.3113G>C p.(Arg1038Pro), 1.0 pt, PMID: 36983702) (PM3_Strong). c.265C>T p.(Arg89Ter) can be classified as at least LP independently (PVS1, PM2_Supporting) c.3113G>C p.(Arg1038Pro) can be classified as at least LP independently (PM2_Supporting, PS3_Moderate, PP3, PM5)
PVS1
The NM_003494.4: c.4756C>T p.(Arg1586Ter) variant in DYSF, which is also known as NM_001130987.2: c.4873C>T p.(Arg1625Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 43/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
Not Met criteria codes
PM2
The filtering allele frequency of this variant is 0.0001061 (the upper threshold of the 95% CI of 4/86258 South Asian exome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met).
Curation History
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