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

Variant: NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)

CA1706448

242418 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4ccb8778-2990-44da-8c1a-bc43260e3b99
Approved on: 2025-02-25
Published on: 2025-03-07

HGVS expressions

NM_001130987.2:c.3167G>A
NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)
NC_000002.12:g.71570680G>A
CM000664.2:g.71570680G>A
NC_000002.11:g.71797810G>A
CM000664.1:g.71797810G>A
NC_000002.10:g.71651318G>A
NG_008694.1:g.122058G>A
ENST00000698057.1:c.539G>A
ENST00000258104.8:c.3113G>A
ENST00000410020.8:c.3167G>A
ENST00000258104.7:c.3113G>A
ENST00000394120.6:c.3116G>A
ENST00000409366.5:c.3116G>A
ENST00000409582.7:c.3164G>A
ENST00000409651.5:c.3209G>A
ENST00000409744.5:c.3074G>A
ENST00000409762.5:c.3164G>A
ENST00000410020.7:c.3167G>A
ENST00000410041.1:c.3167G>A
ENST00000413539.6:c.3206G>A
ENST00000429174.6:c.3113G>A
ENST00000461565.1:n.279G>A
NM_001130455.1:c.3116G>A
NM_001130976.1:c.3071G>A
NM_001130977.1:c.3071G>A
NM_001130978.1:c.3113G>A
NM_001130979.1:c.3206G>A
NM_001130980.1:c.3164G>A
NM_001130981.1:c.3164G>A
NM_001130982.1:c.3209G>A
NM_001130983.1:c.3116G>A
NM_001130984.1:c.3074G>A
NM_001130985.1:c.3167G>A
NM_001130986.1:c.3074G>A
NM_001130987.1:c.3167G>A
NM_003494.3:c.3113G>A
NM_001130455.2:c.3116G>A
NM_001130976.2:c.3071G>A
NM_001130977.2:c.3071G>A
NM_001130978.2:c.3113G>A
NM_001130979.2:c.3206G>A
NM_001130980.2:c.3164G>A
NM_001130981.2:c.3164G>A
NM_001130982.2:c.3209G>A
NM_001130983.2:c.3116G>A
NM_001130984.2:c.3074G>A
NM_001130985.2:c.3167G>A
NM_001130986.2:c.3074G>A
NM_003494.4:c.3113G>A
More

Pathogenic

Met criteria codes 5
PP4_Strong PS3_Moderate PP3 PM2_Supporting PM3_Strong
Not Met criteria codes 1
PP1

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.3113G>A variant in DYSF, which is also known as NM_001130987.2: c.3167G>A (p.Arg1056Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1038, p.(Arg1038Gln). This variant has been detected in at least seven patients with features consistent with LGMD (PMID: 36983702, 26404900, 34559919, 14678801, 30919934, 27854218, 21522182), including in a homozygous state (0.5 pts, PMID: 30919934) and confirmed in trans (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 27854218) and in unknown phase (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.25 pts, PMID: 14678801, 26404900; NM_003494.4: c.2077delC p.(His693ThrfsTer4), 0.25 pts, PMID: 21522182) with a variant classified as at least likely pathogenic (PM3_Strong). At least one patient with this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 14678801, 21522182). The filtering allele frequency of this variant is 0.000056915 (the upper threshold of the 95% CI of 50/1111952 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Gln 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 0.94, 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; 02/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3.
Met criteria codes
PP4_Strong
At least one patient with this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 14678801, 21522182).
PS3_Moderate
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Gln protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).
PP3
The computational predictor REVEL gives a score of 0.94, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3).
PM2_Supporting
The filtering allele frequency of this variant is 0.000056915 (the upper threshold of the 95% CI of 50/1111952 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).
PM3_Strong
This variant has been detected in at least seven patients with features consistent withLGMD (PMID: 36983702, 26404900, 34559919, 14678801, 30919934, 27854218, 21522182), including in a homozygous state (0.5 pts, PMID: 30919934) and confirmed in trans (c.2643+1G>A, 1.0 pt, PMID: 27854218) and in unknown phase (c.5979dup p.(Glu1994ArgfsTer3), 0.25 pts, PMID: 14678801, 26404900; c.2077delC p.(His693ThrfsTer4), 0.25 pts, PMID: 21522182) with a variant classified as at least likely pathogenic (PM3_Strong). c.2643+1G>A is approved and published at P c.5979dup, c.2077del are provisionally LP without this observation
Not Met criteria codes
PP1
variants also present in 1 affected family member but phase unknown (PMID: 14678801), so PP1 not met
Curation History
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