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.851C>T (p.Thr284Met)

CA222210

94358 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: dcb5cba5-9433-4e34-8772-e1eefcbe743d
Approved on: 2025-06-17
Published on: 2025-07-08

HGVS expressions

NM_001130987.2:c.851C>T
NM_001130987.2(DYSF):c.851C>T (p.Thr284Met)
NC_000002.12:g.71515714C>T
CM000664.2:g.71515714C>T
NC_000002.11:g.71742844C>T
CM000664.1:g.71742844C>T
NC_000002.10:g.71596352C>T
NG_008694.1:g.67092C>T
ENST00000258104.8:c.755C>T
ENST00000410020.8:c.851C>T
ENST00000258104.7:c.755C>T
ENST00000394120.6:c.758C>T
ENST00000409366.5:c.758C>T
ENST00000409582.7:c.848C>T
ENST00000409651.5:c.851C>T
ENST00000409744.5:c.758C>T
ENST00000409762.5:c.848C>T
ENST00000410020.7:c.851C>T
ENST00000410041.1:c.851C>T
ENST00000413539.6:c.848C>T
ENST00000429174.6:c.755C>T
NM_001130455.1:c.758C>T
NM_001130976.1:c.755C>T
NM_001130977.1:c.755C>T
NM_001130978.1:c.755C>T
NM_001130979.1:c.848C>T
NM_001130980.1:c.848C>T
NM_001130981.1:c.848C>T
NM_001130982.1:c.851C>T
NM_001130983.1:c.758C>T
NM_001130984.1:c.758C>T
NM_001130985.1:c.851C>T
NM_001130986.1:c.758C>T
NM_001130987.1:c.851C>T
NM_003494.3:c.755C>T
NM_001130455.2:c.758C>T
NM_001130976.2:c.755C>T
NM_001130977.2:c.755C>T
NM_001130978.2:c.755C>T
NM_001130979.2:c.848C>T
NM_001130980.2:c.848C>T
NM_001130981.2:c.848C>T
NM_001130982.2:c.851C>T
NM_001130983.2:c.758C>T
NM_001130984.2:c.758C>T
NM_001130985.2:c.851C>T
NM_001130986.2:c.758C>T
NM_003494.4:c.755C>T
More

Pathogenic

Met criteria codes 5
PP4_Strong PS3_Moderate PM3_Strong PM2_Supporting PP3

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.755C>T variant in DYSF, which is also known as NM_001130987.2: c.851C>T p.(Thr284Met), is a missense variant predicted to cause substitution of threonine by methionine at amino acid 252, p.(Thr252Met). This variant has been observed in at least 12 individuals with features consistent with LGMD (PMID: 30564623; 36575883; 34559919; 33927379; 27647186; 21522182; LOVD DYSF_000768), including in a homozygous state in at least two patients without reported familial consanguinity (1.0 pt; PMID: 36575883; 21522182) and in unknown phase with a pathogenic variant in at least two patients (NM_003494.4: c.3790_3797_del p.(Ser1264ValfsTer9), 0.5 pts, PMID: 34559919, LOVD Individual #00375911; NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 30564623, LOVD Individual #00221967) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD/Miyoshi myopathy and significantly reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PP4_Strong; PMID: 21522182). The highest population frequency for this variant in gnomAD v4.1.0 is 0.00004458 (2/44866 East Asian chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Thr252Met protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3). In addition, the computational predictor REVEL gives a score of 0.926, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). 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; 06/17/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3.
Met criteria codes
PP4_Strong
At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD/Miyoshi myopathy and significantly reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PP4_Strong; PMID: 21522182).
PS3_Moderate
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Thr252Met protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3).
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Thr252Met protein did not reach the cell membrane PubMed:35028538
PM3_Strong
This variant has been observed in at least 12 individuals with features consistent with LGMD (PMID: 30564623; 36575883; 34559919; 33927379; 27647186; 21522182; LOVD DYSF_000768), including in a homozygous state in at least two patients without reported familial consanguinity (1.0 pt; PMID: 36575883; 21522182) and in unknown phase with a pathogenic variant in at least two patients (NM_003494.4: c.3790_3797_del p.(Ser1264ValfsTer9), 0.5 pts, PMID: 34559919; LOVD Individual #00375911; NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 30564623; LOVD Individual #00221967) (PM3_Strong). when both variants present in gnomAD v2, confirmed variants in unknown phase not predicted on same haplotype
PM2_Supporting
The highest population frequency for this variant in gnomAD v4.1.0 is 0.00004458 (2/44866 East Asian chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). FAF based on European (non-Finnish) population data also meets criterion
PP3
The computational predictor REVEL gives a score of 0.926, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3).
Curation History
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