Variant: NM_001130987.1(DYSF):c.3105dup(p.Ile1036Hisfs)

Version: 1.1
JSON-LD PDF

CA1706424

498619 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: bb7bc1e7-0f6b-4693-b92f-24e97a193dab

Approved on: 2025-05-28

Published on: 2025-06-06

HGVS expressions

NM_001130987.1(DYSF):c.3105dup(p.Ile1036Hisfs)
NC_000002.12:g.71570618dup
CM000664.2:g.71570618dup
NC_000002.11:g.71797748dup
CM000664.1:g.71797748dup
NC_000002.10:g.71651256dup
NG_008694.1:g.121996dup
ENST00000698057.1:c.477dup
ENST00000258104.8:c.3051dup
ENST00000410020.8:c.3105dup
ENST00000258104.7:c.3051dup
ENST00000394120.6:c.3054dup
ENST00000409366.5:c.3054dup
ENST00000409582.7:c.3102dup
ENST00000409651.5:c.3147dup
ENST00000409744.5:c.3012dup
ENST00000409762.5:c.3102dup
ENST00000410020.7:c.3105dup
ENST00000410041.1:c.3105dup
ENST00000413539.6:c.3144dup
ENST00000429174.6:c.3051dup
ENST00000461565.1:n.217dup
NM_001130455.1:c.3054dup
NM_001130976.1:c.3009dup
NM_001130977.1:c.3009dup
NM_001130978.1:c.3051dup
NM_001130979.1:c.3144dup
NM_001130980.1:c.3102dup
NM_001130981.1:c.3102dup
NM_001130982.1:c.3147dup
NM_001130983.1:c.3054dup
NM_001130984.1:c.3012dup
NM_001130985.1:c.3105dup
NM_001130986.1:c.3012dup
NM_001130987.1:c.3105dup
NM_003494.3:c.3051dup
NM_001130987.2:c.3105dup
NM_001130455.2:c.3054dup
NM_001130976.2:c.3009dup
NM_001130977.2:c.3009dup
NM_001130978.2:c.3051dup
NM_001130979.2:c.3144dup
NM_001130980.2:c.3102dup
NM_001130981.2:c.3102dup
NM_001130982.2:c.3147dup
NM_001130983.2:c.3054dup
NM_001130984.2:c.3012dup
NM_001130985.2:c.3105dup
NM_001130986.2:c.3012dup
NM_003494.4:c.3051dup

Pathogenic

• Met criteria codes: PP4_Strong PVS1 PP1 PM2_Supporting

• Not Met criteria codes: PM3

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 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.3051dup p.(Ile1018HisfsTer14) variant in DYSF, which is also known as NM_001130987.2: c.3105dup p.(Ile1036HisfsTer14), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 29/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in trans with a second presumed diagnostic DYSF variant in a patient who displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong). This variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; PMID: 36983702). The filtering allele frequency of this variant is 0.000028252 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 22/1111934 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). 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; 05/28/2025): PVS1, PP4_Strong, PP1, PM2_Supporting.

Met criteria codes

• PP4_Strong: At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong).
• PVS1: The NM_003494.4: c.3051dup p.(Ile1018HisfsTer14) variant in DYSF, which is also known as NM_001130987.2: c.3105dup p.(Ile1036HisfsTer14), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 29/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
• PP1: This variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID: 36983702).
• PM2_Supporting: The filtering allele frequency of this variant is 0.000028252 (the upper threshold of the 95% CI of 22/1111934 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

Not Met criteria codes

• PM3: This variant has been identified in trans with a presumed diagnostic DYSF variant in a patient with LGMD (PMID: 36983702). In this patient, the frameshift was observed in trans with heterozygous DYSF exon 34 deletion, which is only VUS without counting the evidence from this individual (PVS1_Mod, PM2_Supporting, not counting PP4_Strong, PP1): 0.25 pts