Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001130987.2(DYSF):c.5420G>A (p.Arg1807Gln)

CA1707357

282624 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: 71f89ba6-5f38-4520-af34-1d6d2549ec04

Approved on: 2026-04-30

Published on: 2026-05-07

HGVS expressions

NM_001130987.2(DYSF):c.5420G>A (p.Arg1807Gln)

NM_001130987.2:c.5420G>A

NC_000002.12:g.71667478G>A

CM000664.2:g.71667478G>A

NC_000002.11:g.71894608G>A

CM000664.1:g.71894608G>A

NC_000002.10:g.71748116G>A

NG_008694.1:g.218856G>A

ENST00000698057.1:c.2834G>A

ENST00000698058.1:c.2051G>A

ENST00000698059.1:c.2159G>A

ENST00000258104.8:c.5303G>A

ENST00000410020.8:c.5420G>A

ENST00000258104.7:c.5303G>A

ENST00000394120.6:c.5306G>A

ENST00000409366.5:c.5369G>A

ENST00000409582.7:c.5417G>A

ENST00000409651.5:c.5399G>A

ENST00000409744.5:c.5327G>A

ENST00000409762.5:c.5354G>A

ENST00000410020.7:c.5420G>A

ENST00000410041.1:c.5357G>A

ENST00000413539.6:c.5396G>A

ENST00000429174.6:c.5366G>A

ENST00000479049.6:n.2188G>A

NM_001130455.1:c.5306G>A

NM_001130976.1:c.5261G>A

NM_001130977.1:c.5324G>A

NM_001130978.1:c.5366G>A

NM_001130979.1:c.5396G>A

NM_001130980.1:c.5354G>A

NM_001130981.1:c.5417G>A

NM_001130982.1:c.5399G>A

NM_001130983.1:c.5369G>A

NM_001130984.1:c.5327G>A

NM_001130985.1:c.5357G>A

NM_001130986.1:c.5264G>A

NM_001130987.1:c.5420G>A

NM_003494.3:c.5303G>A

NM_001130455.2:c.5306G>A

NM_001130976.2:c.5261G>A

NM_001130977.2:c.5324G>A

NM_001130978.2:c.5366G>A

NM_001130979.2:c.5396G>A

NM_001130980.2:c.5354G>A

NM_001130981.2:c.5417G>A

NM_001130982.2:c.5399G>A

NM_001130983.2:c.5369G>A

NM_001130984.2:c.5327G>A

NM_001130985.2:c.5357G>A

NM_001130986.2:c.5264G>A

NM_003494.4:c.5303G>A

Pathogenic

PM3 PM5 PP4_Strong PP3 PM2_Supporting

BA1 BS1 PS3 PS1

Evidence Links 0

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

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.5303G>A variant in DYSF, which is also known as NM_001130987.2(DYSF):c.5420G>A p.(Arg1807Gln), is a missense variant predicted to cause the substitution of arginine for glutamine at amino acid position 1768, p.(Arg1768Gln). This variant has been identified in at least three individuals with features consistent with LGMD, including in a homozygous state without reported consanguinity in one patient (0.5 pts, PMID: 33927379, LOVD Individual #00327538) and confirmed in trans with a pathogenic variant in one patient (NM_003494.4: c.1284+2T>C, 1.0 pt, PMID: 32751317) (PM3). In the third patient, it was reported in unknown phase with two other DYSF missense variants (Jain Foundation Dysferlin Registry internal data communication). The homozygous patient was referred for diagnostic sequencing of DYSF by a neurologist due to a clinical suspicion of dysferlinopathy. Absent dysferlin expression in skeletal muscle was also confirmed in this individual (PMID: 33927379, LOVD Individual #00327538; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000074234 (72/1180030 European (non-Finnish chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) (PM2_Supporting). The REVEL score of this variant is 0.843, which is above the threshold (≥0.7), evidence that correlates with impact on DYSF function (PP3). In addition, another missense change at the same position, NM_003494.4: c.5302C>T p.(Arg1768Trp), is classified as pathogenic for 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 2.0.0; 04/30/2026): PM3, PP4_Strong, PM2_Supporting, PP3, PM5.

PM3

This variant has been identified in at least three individuals with features consistent with LGMD, including in a homozygous state without reported consanguinity in one patient (0.5 pts, PMID: 33927379, LOVD Individual #00327538) and confirmed in trans with a pathogenic variant in one patient (NM_003494.4: c.1284+2T>C, 1.0 pt, PMID: 32751317) (PM3). In the third patient, it was reported in unknown phase with two other DYSF missense variants (Jain Foundation Dysferlin Registry internal data communication).

PM5

Another missense change at the same position, NM_003494.4: c.5302C>T p.(Arg1768Trp), is classified as pathogenic for limb girdle muscular dystrophy by the LGMD VCEP (PM5). c.5302C>T p.(Arg1768Trp) is approved at P by the VCEP without use of PM5: PM3, PP4_Strong, PP1, PS3_Moderate, PP3 PP3 applies to both the curated variant and the comparison variant neither are predicted to effect splicing do not affect first or last residue of an exon other variants at this position: c.5303G>T p.(Arg1768Leu) LOVD Individual #00313713 / Fam47Pat1 from Magri et al. (2015) with c.2200_2204del p.(Thr734Profs*18)

PP4_Strong

This variant was reported in a homozygous state in an individual referred for diagnostic sequencing of DYSF by a neurologist due to a clinical suspicion of dysferlinopathy. Absent dysferlin expression in skeletal muscle was also confirmed in this individual (PMID: 33927379, LOVD Individual #00327538; PP4_Strong).

PP3

The REVEL score of this variant is 0.843, which is above the threshold (≥0.7), evidence that correlates with impact on DYSF function (PP3). SpliceAI 0

PM2_Supporting

The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000074234 (72/1180030 European (non-Finnish chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) (PM2_Supporting).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

Arg1768Gln not evaluated in Tominaga et al. (2022)

PS1

No other pathogenic variant was found to lead to the same amino acid change (PS1 Not Met).

Curation History

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