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 label mismatch: DYSF vs undefined
  • 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.268C>T (p.Arg90Ter)

CA275254

197217 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 8012ad07-ac5b-4609-a73d-0855852174e7
Approved on: 2025-04-16
Published on: 2025-05-16

HGVS expressions

NM_001130987.2:c.268C>T
NM_001130987.2(DYSF):c.268C>T (p.Arg90Ter)
NC_000002.12:g.71503242C>T
CM000664.2:g.71503242C>T
NC_000002.11:g.71730372C>T
CM000664.1:g.71730372C>T
NC_000002.10:g.71583880C>T
NG_008694.1:g.54620C>T
ENST00000258104.8:c.265C>T
ENST00000410020.8:c.268C>T
ENST00000258104.7:c.265C>T
ENST00000394120.6:c.268C>T
ENST00000409366.5:c.268C>T
ENST00000409582.7:c.265C>T
ENST00000409651.5:c.268C>T
ENST00000409744.5:c.268C>T
ENST00000409762.5:c.265C>T
ENST00000410020.7:c.268C>T
ENST00000410041.1:c.268C>T
ENST00000413539.6:c.265C>T
ENST00000429174.6:c.265C>T
NM_001130455.1:c.268C>T
NM_001130976.1:c.265C>T
NM_001130977.1:c.265C>T
NM_001130978.1:c.265C>T
NM_001130979.1:c.265C>T
NM_001130980.1:c.265C>T
NM_001130981.1:c.265C>T
NM_001130982.1:c.268C>T
NM_001130983.1:c.268C>T
NM_001130984.1:c.268C>T
NM_001130985.1:c.268C>T
NM_001130986.1:c.268C>T
NM_001130987.1:c.268C>T
NM_003494.3:c.265C>T
NM_001130455.2:c.268C>T
NM_001130976.2:c.265C>T
NM_001130977.2:c.265C>T
NM_001130978.2:c.265C>T
NM_001130979.2:c.265C>T
NM_001130980.2:c.265C>T
NM_001130981.2:c.265C>T
NM_001130982.2:c.268C>T
NM_001130983.2:c.268C>T
NM_001130984.2:c.268C>T
NM_001130985.2:c.268C>T
NM_001130986.2:c.268C>T
NM_003494.4:c.265C>T
More

Pathogenic

Met criteria codes 4
PM2_Supporting PM3 PP4_Strong PVS1

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.265C>T p.(Arg89Ter) variant in DYSF, which is also known as NM_001130987.2: c.268C>T (p.Arg90Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/55, 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 at least five unrelated individuals with features consistent with LGMD (PMID: 23641709; 18853459; 21173544; 19493611), including in a homozygous state in two patients, one with known familial consanguinity (0.75 pts, PMID: 18853459; 19493611). It has also been observed in unknown phase with a pathogenic variant (NM_003494.4: c.3126G>A p.(Trp1042Ter), 0.5 pts, PMID: 18853459) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 18853459; 19493611; PP4_Strong). The highest population minor allele frequency is 0.00005974 in gnomAD v4.1.0 exomes (2/33480 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, 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; 04/16/2025): PVS1, PM3, PP4_Strong, PM2_Supporting.
Met criteria codes
PM2_Supporting
The highest population minor allele frequency is 0.00005974 in gnomAD v4.1.0 exomes (2/33480 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Note: PM2_Supporting is still met if the FAF is calculated for the European (non-Finnish) exome data (4/1111974 exome alleles = FAF of 0.000008)
PM3
This variant has been identified in at least five unrelated individuals with features consistent with LGMD (PMID: 23641709, 18853459, 21173544, 19493611), including in a homozygous state in two patients, one with known familial consanguinity (0.75 pts, PMID: 18853459, 19493611). It has also been observed in unknown phase with a pathogenic variant (NM_003494.4: c.3126G>A p.(Trp1042Ter), 0.5 pts, PMID: 18853459) (PM3). The classification of c.3126G>A p.(Trp1042Ter) as Pathogenic has been approved and did not make use of this case.
PP4_Strong
At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 18853459, 19493611; PP4_Strong).
PVS1
The NM_003494.4: c.265C>T p.(Arg89Ter) variant in DYSF, which is also known as NM_001130987.2: c.268C>T (p.Arg90Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.