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.991G>T (p.Gly331Trp)

CA253918

6682 (ClinVar)

Gene: DYSF (HGNC:8291)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: f55c5259-c60b-4607-a58c-f357332155c9
Approved on: 2025-07-29
Published on: 2025-08-14

HGVS expressions

NM_001130987.2(DYSF):c.991G>T (p.Gly331Trp)
NM_001130987.2:c.991G>T
NC_000002.12:g.71517028G>T
CM000664.2:g.71517028G>T
NC_000002.11:g.71744158G>T
CM000664.1:g.71744158G>T
NC_000002.10:g.71597666G>T
NG_008694.1:g.68406G>T
ENST00000258104.8:c.895G>T
ENST00000410020.8:c.991G>T
ENST00000258104.7:c.895G>T
ENST00000394120.6:c.898G>T
ENST00000409366.5:c.898G>T
ENST00000409582.7:c.988G>T
ENST00000409651.5:c.991G>T
ENST00000409744.5:c.898G>T
ENST00000409762.5:c.988G>T
ENST00000410020.7:c.991G>T
ENST00000410041.1:c.991G>T
ENST00000413539.6:c.988G>T
ENST00000429174.6:c.895G>T
NM_001130455.1:c.898G>T
NM_001130976.1:c.895G>T
NM_001130977.1:c.895G>T
NM_001130978.1:c.895G>T
NM_001130979.1:c.988G>T
NM_001130980.1:c.988G>T
NM_001130981.1:c.988G>T
NM_001130982.1:c.991G>T
NM_001130983.1:c.898G>T
NM_001130984.1:c.898G>T
NM_001130985.1:c.991G>T
NM_001130986.1:c.898G>T
NM_001130987.1:c.991G>T
NM_003494.3:c.895G>T
NM_001130455.2:c.898G>T
NM_001130976.2:c.895G>T
NM_001130977.2:c.895G>T
NM_001130978.2:c.895G>T
NM_001130979.2:c.988G>T
NM_001130980.2:c.988G>T
NM_001130981.2:c.988G>T
NM_001130982.2:c.991G>T
NM_001130983.2:c.898G>T
NM_001130984.2:c.898G>T
NM_001130985.2:c.991G>T
NM_001130986.2:c.898G>T
NM_003494.4:c.895G>T
More

Pathogenic

Met criteria codes 7
PM3_Supporting PM2_Supporting PP1 PP3 PM5 PS3_Moderate PP4_Strong

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 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.895G>T variant in DYSF, which is also known as NM_001130987.2: c.991G>T p.(Gly331Trp), is a missense variant predicted to cause substitution of glycine by tryptophan at amino acid 299, p.(Gly299Trp). This variant has been reported in a homozygous state in at least one individual with clinical features of LGMD (0.5 pts, PMID: 18306167, 28877744; PM3_Supporting). At least one patient had a clinical diagnosis or suspicion of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 28877744; PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 18306167; PP1). The highest frequency for this variant in gnomAD v4.1.0 is 0.00001098 in the South Asian population (1/91082 alleles), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). The computational predictor REVEL gives a score of 0.968, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In addition, another missense variant at the same codon, p.(Gly299Arg) resulting from either c.895G>A or c.895G>C, has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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; 07/29/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5.
Met criteria codes
PM3_Supporting
This variant has been reported in a homozygous state at least one individual with clinical features consistent with LGMD and without reported familial consanguinity (0.5 pts, PMID: 18306167, 28877744; PM3_Supporting). potential overlap between Harris and Spuler reports, so only counting as one
PM2_Supporting
The highest frequency for this variant in gnomAD v4.1.0 is 0.00001098 in the South Asian population (1/91082 alleles), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting).
PP1
This variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 18306167; PP1).
PP3
The computational predictor REVEL gives a score of 0.968, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3).
PM5
Another missense variant at the same codon, p.(Gly299Arg) resulting from either c.895G>A or c.895G>C, has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). no benign variation at this residue comparison variants: c.895G>A p.(Gly299Arg) REVEL: 0.968 SpliceAI: 0.0600 P without use of PM5 for c.896G>A p.(Gly299Glu): PM3, PP4_Strong, PP1, PM2_Supporting, PS3_Moderate, PP3 c.895G>C p.(Gly299Arg) REVEL: 0.968 Splice AI 0.08 P without use of PM5 for c.896G>A p.(Gly299Glu): PM3_Strong, PP4, PM2_Supporting, PS3_Moderate, PP3, PS1 (for c.895G>A)
PS3_Moderate
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Trp protein did not reach the cell membrane PubMed:35028538
PP4_Strong
At least one patient had a clinical diagnosis or suspicion of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 28877744; PP4_Strong).
Curation History
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