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.3175C>T (p.Arg1059Cys)

CA1706454

286743 (ClinVar)

Gene: DYSF (HGNC:8291)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: 4ec67d01-004b-4caf-9f85-df183fd6da2c
Approved on: 2026-04-28
Published on: 2026-05-07

HGVS expressions

NM_001130987.2(DYSF):c.3175C>T (p.Arg1059Cys)
NM_001130987.2:c.3175C>T
NC_000002.12:g.71570688C>T
CM000664.2:g.71570688C>T
NC_000002.11:g.71797818C>T
CM000664.1:g.71797818C>T
NC_000002.10:g.71651326C>T
NG_008694.1:g.122066C>T
ENST00000698057.1:c.547C>T
ENST00000258104.8:c.3121C>T
ENST00000410020.8:c.3175C>T
ENST00000258104.7:c.3121C>T
ENST00000394120.6:c.3124C>T
ENST00000409366.5:c.3124C>T
ENST00000409582.7:c.3172C>T
ENST00000409651.5:c.3217C>T
ENST00000409744.5:c.3082C>T
ENST00000409762.5:c.3172C>T
ENST00000410020.7:c.3175C>T
ENST00000410041.1:c.3175C>T
ENST00000413539.6:c.3214C>T
ENST00000429174.6:c.3121C>T
ENST00000461565.1:n.287C>T
NM_001130455.1:c.3124C>T
NM_001130976.1:c.3079C>T
NM_001130977.1:c.3079C>T
NM_001130978.1:c.3121C>T
NM_001130979.1:c.3214C>T
NM_001130980.1:c.3172C>T
NM_001130981.1:c.3172C>T
NM_001130982.1:c.3217C>T
NM_001130983.1:c.3124C>T
NM_001130984.1:c.3082C>T
NM_001130985.1:c.3175C>T
NM_001130986.1:c.3082C>T
NM_001130987.1:c.3175C>T
NM_003494.3:c.3121C>T
NM_001130455.2:c.3124C>T
NM_001130976.2:c.3079C>T
NM_001130977.2:c.3079C>T
NM_001130978.2:c.3121C>T
NM_001130979.2:c.3214C>T
NM_001130980.2:c.3172C>T
NM_001130981.2:c.3172C>T
NM_001130982.2:c.3217C>T
NM_001130983.2:c.3124C>T
NM_001130984.2:c.3082C>T
NM_001130985.2:c.3175C>T
NM_001130986.2:c.3082C>T
NM_003494.4:c.3121C>T
More

Likely Pathogenic

Met criteria codes 3
PP3 PM3 PP4_Strong
Not Met criteria codes 5
PM5 PM2 BS1 BS3 PS3

Evidence Links 1

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.3121C>T variant in DYSF, which is also known as NM_001130987.2: c.3175C>T p.(Arg1059Cys), is a missense variant predicted to cause substitution of arginine to cysteine at amino acid 1041, p.(Arg1041Cys). This variant has been reported in at least four individuals with suspected LGMD including in a homozygous state in two individuals (1 pt, PMID: 15469449, 27602406) and with a second variant in unknown phase (c.2077delC p.(His693ThrfsTer4), 0.5 pts, PMID: 27602406) (PM3). The filtering allele frequency of this variant is 0.0002886 in gnomAD v4.1.1 (upper threshold of the 95% CI of 310/1179972 European (non-Finnish) chromosomes) which is greater than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting and BS1 not applicable). The computational predictor REVEL gives a score of 0.82, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). At least one patient with suspected LGMD had this variant and a second presumed diagnostic DYSF variant and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 15469449, 27602406; PP4_Strong). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Arg1041Cys protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/28/2026): PP4_strong, PM3, PP3.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.82, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). Splice AI: 0.00
PM3
This variant has been reported in at least four individuals with suspected LGMD including in a homozygous state in two individuals (1 pt, PMID: 15469449, 27602406) and with a second variant in unknown phase (c.2077delC p.(His693ThrfsTer4), 0.5 pts, PMID: 27602406) (PM3).
PP4_Strong
At least one patient with suspected LGMD had this variant and a second presumed diagnostic DYSF variant and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 15469449, 27602406; PP4_Strong).
Not Met criteria codes
PM5
Another missense variant at this position classified as VUS by VCEP (c.3122G>A p.(Arg1041His).
PM2
The filtering allele frequency of this variant is 0.0002886 in gnomAD v4.1.1 (upper threshold of the 95% CI of 310/1179972 European (non-Finnish) chromosomes) which is greater than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting and BS1 not applicable).
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Arg1041Cys protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met).
Functional in both 2A and ICC assays of dysferlin membrane localization. BS3 not applicable. PubMed:35028538
PS3
Functional in both 2A and ICC assays of dysferlin membrane localization. BS3 not applicable. PubMed:35028538
Curation History
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