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.1225C>T (p.Arg409Ter)

CA1705654

265487 (ClinVar)

Gene: DYSF (HGNC:8291)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: 07b0d7cb-9a41-40f0-a2a3-3665888ce2f6
Approved on: 2026-05-01
Published on: 2026-05-07

HGVS expressions

NM_001130987.2(DYSF):c.1225C>T (p.Arg409Ter)
NM_001130987.2:c.1225C>T
NC_000002.12:g.71526295C>T
CM000664.2:g.71526295C>T
NC_000002.11:g.71753425C>T
CM000664.1:g.71753425C>T
NC_000002.10:g.71606933C>T
NG_008694.1:g.77673C>T
ENST00000258104.8:c.1129C>T
ENST00000410020.8:c.1225C>T
ENST00000258104.7:c.1129C>T
ENST00000394120.6:c.1132C>T
ENST00000409366.5:c.1132C>T
ENST00000409582.7:c.1222C>T
ENST00000409651.5:c.1225C>T
ENST00000409744.5:c.1132C>T
ENST00000409762.5:c.1222C>T
ENST00000410020.7:c.1225C>T
ENST00000410041.1:c.1225C>T
ENST00000413539.6:c.1222C>T
ENST00000429174.6:c.1129C>T
NM_001130455.1:c.1132C>T
NM_001130976.1:c.1129C>T
NM_001130977.1:c.1129C>T
NM_001130978.1:c.1129C>T
NM_001130979.1:c.1222C>T
NM_001130980.1:c.1222C>T
NM_001130981.1:c.1222C>T
NM_001130982.1:c.1225C>T
NM_001130983.1:c.1132C>T
NM_001130984.1:c.1132C>T
NM_001130985.1:c.1225C>T
NM_001130986.1:c.1132C>T
NM_001130987.1:c.1225C>T
NM_003494.3:c.1129C>T
NM_001130455.2:c.1132C>T
NM_001130976.2:c.1129C>T
NM_001130977.2:c.1129C>T
NM_001130978.2:c.1129C>T
NM_001130979.2:c.1222C>T
NM_001130980.2:c.1222C>T
NM_001130981.2:c.1222C>T
NM_001130982.2:c.1225C>T
NM_001130983.2:c.1132C>T
NM_001130984.2:c.1132C>T
NM_001130985.2:c.1225C>T
NM_001130986.2:c.1132C>T
NM_003494.4:c.1129C>T
More

Pathogenic

Met criteria codes 2
PVS1 PP4_Strong
Not Met criteria codes 3
PP1 PM3 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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Limb Girdle Muscular Dystrophy VCEP
The NM_003494.4: c.1129C>T p.(Arg377Ter) variant in DYSF, which is also known as NM_001130987.2: c.1225C>T p.(Arg409Ter), is a nonsense variant that introduces a premature stop codon in exon 12/55, 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 three unrelated individuals with LGMD (PMID: 33250842, 22297152; ClinVar SCV004292580.2 internal data communication), including in unconfirmed phase with a presumed diagnostic variant in two patients and in a homozygous state in one patient with possible familial consanguinity (0.25 pts, PMID: 33250842). At least one patient homozygous for this variant showed both progressive proximal muscle weakness and absent dysferlin expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 33250842; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency is 0.00017529 in gnomAD v4.1.0 (5/60010 Admixed American alleles), which is greater than the threshold for PM2_Supporting (criterion 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 LGMD VCEP (specifications v2.0.0; 05/01/2026): PVS1, PP4_Strong.
Met criteria codes
PVS1
The NM_003494.4: c.1129C>T p.(Arg377Ter) variant in DYSF, which is also known as NM_001130987.2: c.1225C>T p.(Arg409Ter), is a nonsense variant that introduces a premature stop codon in exon 12/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
PP4_Strong
At least one patient homozygous for this variant showed both progressive proximal muscle weakness and absent dysferlin expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 33250842; PP4_Strong).
Not Met criteria codes
PP1
Likely one affected family member with the same genotype, but phase not confirmed (ClinVar SCV004292580.2 internal data communication).
PM3
This variant has been reported in at least three unrelated individuals with LGMD (PMID: 33250842, 22297152; ClinVar SCV004292580.2 internal data communication), including in unconfirmed phase with a presumed diagnostic variant in two patients and in a homozygous state in one patient with possible familial consanguinity (0.25 pts, PMID: 33250842). LOVD DYSF_000796: 2 single hits in Nallamilli et al. additional weight from PM3 not need for P classification
PM2
The upper bound of the 95% confidence interval of the Grpmax variant allele frequency is 0.00017529 in gnomAD v4.1.0 (5/60010 Admixed American alleles), which is greater than the threshold for PM2_Supporting (criterion not met).
Curation History
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