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.1273C>T (p.Gln425Ter)

CA347213670

429885 (ClinVar)

Gene: DYSF (HGNC:8291)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: cea3f16a-8c8c-4dcd-844b-2888928e487a
Approved on: 2025-07-29
Published on: 2025-08-14

HGVS expressions

NM_001130987.2:c.1273C>T
NM_001130987.2(DYSF):c.1273C>T (p.Gln425Ter)
NC_000002.12:g.71526343C>T
CM000664.2:g.71526343C>T
NC_000002.11:g.71753473C>T
CM000664.1:g.71753473C>T
NC_000002.10:g.71606981C>T
NG_008694.1:g.77721C>T
ENST00000258104.8:c.1177C>T
ENST00000410020.8:c.1273C>T
ENST00000258104.7:c.1177C>T
ENST00000394120.6:c.1180C>T
ENST00000409366.5:c.1180C>T
ENST00000409582.7:c.1270C>T
ENST00000409651.5:c.1273C>T
ENST00000409744.5:c.1180C>T
ENST00000409762.5:c.1270C>T
ENST00000410020.7:c.1273C>T
ENST00000410041.1:c.1273C>T
ENST00000413539.6:c.1270C>T
ENST00000429174.6:c.1177C>T
NM_001130455.1:c.1180C>T
NM_001130976.1:c.1177C>T
NM_001130977.1:c.1177C>T
NM_001130978.1:c.1177C>T
NM_001130979.1:c.1270C>T
NM_001130980.1:c.1270C>T
NM_001130981.1:c.1270C>T
NM_001130982.1:c.1273C>T
NM_001130983.1:c.1180C>T
NM_001130984.1:c.1180C>T
NM_001130985.1:c.1273C>T
NM_001130986.1:c.1180C>T
NM_001130987.1:c.1273C>T
NM_003494.3:c.1177C>T
NM_001130455.2:c.1180C>T
NM_001130976.2:c.1177C>T
NM_001130977.2:c.1177C>T
NM_001130978.2:c.1177C>T
NM_001130979.2:c.1270C>T
NM_001130980.2:c.1270C>T
NM_001130981.2:c.1270C>T
NM_001130982.2:c.1273C>T
NM_001130983.2:c.1180C>T
NM_001130984.2:c.1180C>T
NM_001130985.2:c.1273C>T
NM_001130986.2:c.1180C>T
NM_003494.4:c.1177C>T
More

Pathogenic

Met criteria codes 4
PM3_Supporting PP4_Strong PVS1 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.1177C>T p.(Glu393Ter) variant in DYSF, which is also known as NM_001130987.2: c.1273C>T p.(Gln425Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified with a second DYSF variant in at least three unrelated individuals with features consistent with LGMD (PMID: 18853459, 33610434; LOVD DYSF_000044), including in unconfirmed phase with a pathogenic variant (NM_003494.4: c.1180+5G>A, 0.5 pts, LOVD Individual #00215246; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 33610434). The highest population allele frequency of this variant in gnomAD v.1.0 is 0.00001352 (1/73984 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) (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; 07/29/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting.
Met criteria codes
PM3_Supporting
This variant has been identified with a second DYSF variant in at least three unrelated individuals with features consistent with LGMD (PMID: 18853459, 33610434; LOVD DYSF_000044), including in unconfirmed phase with a pathogenic variant (NM_003494.4: c.1180+5G>A, 0.5 pts, LOVD Individual #00215246; PM3_Supporting). c.1180+5G>A is P without evidence from this case, predicted on a different haplotype from the curated variant
PP4_Strong
At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 33610434). PMID: 33610434 Moore et al. (2021) patient 162: LGMDR2 clinical diagnosis, absent dysferlin expression in skeletal muscle by IHC and WB. c.1177C>T p.(Glu393Ter) in unknown phase with c.1168G>T p.(Asp390Tyr), which is not yet curated and is not in ClinVar but is absent from gnomAD v4 (BA1, BS1 not applicable).
PVS1
The NM_003494.4: c.1177C>T p.(Glu393Ter) variant in DYSF, which is also known as NM_001130987.2: c.1273C>T p.(Gln425Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
PM2_Supporting
The highest population allele frequency of this variant in gnomAD v.1.0 is 0.00001352 (1/73984 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). PM2_Supporting also met with FAF from European (non-Finnish) exome chromosomes 0.000011841 (the upper threshold of the 95% CI of 7/1110352)
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.
ClinGen Terms of Use.
¤ Powered by BCM's Genboree.