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.1915G>A (p.Gly639Arg)

CA10606091

288438 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 84b2afa7-4c91-418c-87cf-ff0ea150739d
Approved on: 2025-04-03
Published on: 2025-06-17

HGVS expressions

NM_001130987.2:c.1915G>A
NM_001130987.2(DYSF):c.1915G>A (p.Gly639Arg)
NC_000002.12:g.71553119G>A
CM000664.2:g.71553119G>A
NC_000002.11:g.71780249G>A
CM000664.1:g.71780249G>A
NC_000002.10:g.71633757G>A
NG_008694.1:g.104497G>A
ENST00000258104.8:c.1861G>A
ENST00000410020.8:c.1915G>A
ENST00000258104.7:c.1861G>A
ENST00000394120.6:c.1864G>A
ENST00000409366.5:c.1864G>A
ENST00000409582.7:c.1912G>A
ENST00000409651.5:c.1957G>A
ENST00000409744.5:c.1822G>A
ENST00000409762.5:c.1912G>A
ENST00000410020.7:c.1915G>A
ENST00000410041.1:c.1915G>A
ENST00000413539.6:c.1954G>A
ENST00000429174.6:c.1861G>A
NM_001130455.1:c.1864G>A
NM_001130976.1:c.1819G>A
NM_001130977.1:c.1819G>A
NM_001130978.1:c.1861G>A
NM_001130979.1:c.1954G>A
NM_001130980.1:c.1912G>A
NM_001130981.1:c.1912G>A
NM_001130982.1:c.1957G>A
NM_001130983.1:c.1864G>A
NM_001130984.1:c.1822G>A
NM_001130985.1:c.1915G>A
NM_001130986.1:c.1822G>A
NM_001130987.1:c.1915G>A
NM_003494.3:c.1861G>A
NM_001130455.2:c.1864G>A
NM_001130976.2:c.1819G>A
NM_001130977.2:c.1819G>A
NM_001130978.2:c.1861G>A
NM_001130979.2:c.1954G>A
NM_001130980.2:c.1912G>A
NM_001130981.2:c.1912G>A
NM_001130982.2:c.1957G>A
NM_001130983.2:c.1864G>A
NM_001130984.2:c.1822G>A
NM_001130985.2:c.1915G>A
NM_001130986.2:c.1822G>A
NM_003494.4:c.1861G>A
More

Pathogenic

Met criteria codes 6
PS3_Moderate PP1 PP3 PP4_Strong PM3_Strong PM2_Supporting

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.1861G>A variant in DYSF, which is also known as NM_001130987.2: c.1915G>A (p.Gly639Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 621, p.(Gly621Arg). This variant has been reported in at least four patients with dysferlinopathy (PMID: 16100712, 19528035, 21522182, 36983702), including in trans with a pathogenic variant in at least two individuals (NM_003494.4: c.5509G>A p.(Asp1837Asn), 1.0 pt, PMID: 21522182; NM_003494.4: c.5668-7G>A p.(Lys1889insTrpfsTer56, 1.0 pt, PMID: 16100712) (PM3_Strong). At least one of these patients displayed progressive muscle weakness and absent dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 16100712, 21522182, 36983702) (PP4_Strong). This variant was also shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 36983702; PP1). The highest population alternate allele frequency of this variant is 0.00002236 (1/44722 Admixed American 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 Gly621Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.88, 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; 04/03/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PM2_Supporting, PP3.
Met criteria codes
PS3_Moderate
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly621Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).
PP1
This variant was shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 36983702; PP1).
PP3
The computational predictor REVEL gives a score of 0.88, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). not in a splice region
PP4_Strong
At least one of these patients displayed progressive muscle weakness and absent dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 16100712, 21522182, 36983702) (PP4_Strong).
PM3_Strong
This variant has been reported in at least four patients with dysferlinopathy (PMID: 16100712, 19528035, 21522182, 36983702), including in trans with pathogenic variants 5509G>A p.(Asp1837Asn) (1 pt, PMID: 21522182) and 5668-7G>A p.(Lys1889insTrpfsTer56) (1 pt, PMID: 16100712) (PM3_strong).
PM2_Supporting
The highest population alternate allele frequency of this variant is 0.00002236 (1/44722 Admixed American exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).
Curation History
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