Variant: NM_001130987.2(DYSF):c.1116C>A (p.Ser372Arg)

CA347212168

551891 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 7d2f00d1-0b3d-4bc1-8506-119add3f23f7

Approved on: 2025-09-17

Published on: 2025-10-09

HGVS expressions

NM_001130987.2:c.1116C>A
NM_001130987.2(DYSF):c.1116C>A (p.Ser372Arg)
NC_000002.12:g.71520871C>A
CM000664.2:g.71520871C>A
NC_000002.11:g.71748001C>A
CM000664.1:g.71748001C>A
NC_000002.10:g.71601509C>A
NG_008694.1:g.72249C>A
ENST00000258104.8:c.1020C>A
ENST00000410020.8:c.1116C>A
ENST00000258104.7:c.1020C>A
ENST00000394120.6:c.1023C>A
ENST00000409366.5:c.1023C>A
ENST00000409582.7:c.1113C>A
ENST00000409651.5:c.1116C>A
ENST00000409744.5:c.1023C>A
ENST00000409762.5:c.1113C>A
ENST00000410020.7:c.1116C>A
ENST00000410041.1:c.1116C>A
ENST00000413539.6:c.1113C>A
ENST00000429174.6:c.1020C>A
NM_001130455.1:c.1023C>A
NM_001130976.1:c.1020C>A
NM_001130977.1:c.1020C>A
NM_001130978.1:c.1020C>A
NM_001130979.1:c.1113C>A
NM_001130980.1:c.1113C>A
NM_001130981.1:c.1113C>A
NM_001130982.1:c.1116C>A
NM_001130983.1:c.1023C>A
NM_001130984.1:c.1023C>A
NM_001130985.1:c.1116C>A
NM_001130986.1:c.1023C>A
NM_001130987.1:c.1116C>A
NM_003494.3:c.1020C>A
NM_001130455.2:c.1023C>A
NM_001130976.2:c.1020C>A
NM_001130977.2:c.1020C>A
NM_001130978.2:c.1020C>A
NM_001130979.2:c.1113C>A
NM_001130980.2:c.1113C>A
NM_001130981.2:c.1113C>A
NM_001130982.2:c.1116C>A
NM_001130983.2:c.1023C>A
NM_001130984.2:c.1023C>A
NM_001130985.2:c.1116C>A
NM_001130986.2:c.1023C>A
NM_003494.4:c.1020C>A

Pathogenic

• Met criteria codes: PP4_Strong PS3_Moderate PM3_Strong PM2_Supporting

• Not Met criteria codes: PP3 PM5

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

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.1020C>A variant in DYSF, which is also known as NM_001130987.2: c.1116C>A p.(Ser372Arg), is a missense variant predicted to cause substitution of serine by arginine at amino acid 340, p.(Ser340Arg). This variant has been reported in at least five individuals with features consistent with LGMD or dysferlinopathy (PMID: 26404900, 19528035, 21522182; LOVD DYSF_000360; Jain Foundation Dysferlin Registry), including in a homozygous state in two individuals with known or likely familial consanguinity (0.25 pts x2, Jain Foundation Dysferlin Registry internal data communication) and confirmed in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.1254del, 1.0 pt, PMID: 26404900; NM_003494.4: c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 21522182) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin expression in skeletal muscle (PMID: 21522182; PP4_Strong). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00002196 (2/91084 South Asian chromosomes), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.695, which is below the LGMD VCEP threshold of ≥0.70 for PP3 (criterion not met), but immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Ser340Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). 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; 09/17/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate.

Met criteria codes

• PP4_Strong: At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin expression in skeletal muscle (PMID: 21522182; PP4_Strong).
• PS3_Moderate: Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Ser340Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate).
• PM3_Strong: This variant has been reported in at least five individuals with features consistent with LGMD or dysferlinopathy (PMID: 26404900, 19528035, 21522182; LOVD DYSF_000360; Jain Foundation Dysferlin Registry), including in a homozygous state in two individuals with known or possible familial consanguinity (0.25 pts x2, Jain Foundation Dysferlin Registry internal data communication) and confirmed in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.1254del, 1.0 pt, PMID: 26404900; NM_003494.4: c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 21522182) (PM3_Strong). Both c.1254del and c.3504dup are independently classified as at least LP.
• PM2_Supporting: The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00002196 (2/91084 South Asian chromosomes), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.695, which is below the LGMD VCEP threshold of ≥0.70 for PP3 (criterion not met). Not in a splice region, Splice AI 0.07.
• PM5: The REVEL score for the missense variant under curation is not >0.7, so PM5 cannot be applied.