Variant: NM_001130987.2(DYSF):c.5884+6C>T

Version: 1.0
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CA1707525

704394 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 08bdfa2a-f514-4cf5-9c87-99aa72b5a292

Approved on: 2025-09-30

Published on: 2025-10-09

HGVS expressions

NM_001130987.2:c.5884+6C>T
NM_001130987.2(DYSF):c.5884+6C>T
NC_000002.12:g.71674302C>T
CM000664.2:g.71674302C>T
NC_000002.11:g.71901432C>T
CM000664.1:g.71901432C>T
NC_000002.10:g.71754940C>T
NG_008694.1:g.225680C>T
ENST00000698057.1:c.3298+6C>T
ENST00000698058.1:c.2515+6C>T
ENST00000698059.1:c.2623+6C>T
ENST00000258104.8:c.5767+6C>T
ENST00000410020.8:c.5884+6C>T
ENST00000258104.7:c.5767+6C>T
ENST00000394120.6:c.5770+6C>T
ENST00000409366.5:c.5833+6C>T
ENST00000409582.7:c.5881+6C>T
ENST00000409651.5:c.5863+6C>T
ENST00000409744.5:c.5791+6C>T
ENST00000409762.5:c.5818+6C>T
ENST00000410020.7:c.5884+6C>T
ENST00000410041.1:c.5821+6C>T
ENST00000413539.6:c.5860+6C>T
ENST00000429174.6:c.5830+6C>T
ENST00000479049.6:n.2652+6C>T
NM_001130455.1:c.5770+6C>T
NM_001130976.1:c.5725+6C>T
NM_001130977.1:c.5788+6C>T
NM_001130978.1:c.5830+6C>T
NM_001130979.1:c.5860+6C>T
NM_001130980.1:c.5818+6C>T
NM_001130981.1:c.5881+6C>T
NM_001130982.1:c.5863+6C>T
NM_001130983.1:c.5833+6C>T
NM_001130984.1:c.5791+6C>T
NM_001130985.1:c.5821+6C>T
NM_001130986.1:c.5728+6C>T
NM_001130987.1:c.5884+6C>T
NM_003494.3:c.5767+6C>T
NM_001130455.2:c.5770+6C>T
NM_001130976.2:c.5725+6C>T
NM_001130977.2:c.5788+6C>T
NM_001130978.2:c.5830+6C>T
NM_001130979.2:c.5860+6C>T
NM_001130980.2:c.5818+6C>T
NM_001130981.2:c.5881+6C>T
NM_001130982.2:c.5863+6C>T
NM_001130983.2:c.5833+6C>T
NM_001130984.2:c.5791+6C>T
NM_001130985.2:c.5821+6C>T
NM_001130986.2:c.5728+6C>T
NM_003494.4:c.5767+6C>T

Benign

• Met criteria codes: BP7_Strong BA1 BS3 BP4

• Not Met criteria codes: PP4 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 2.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.5767+6C>T variant in DYSF, which is also known as NM_001130987.2: c.5884+6C>T, occurs within the splice donor motif of exon 51. The Grpmax FAF of this variant is 0.004287 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 216/44886 East Asian alleles), which is greater than the ClinGen LGMD VCEP threshold for BA1 (>0.003), meeting this criterion (BA1). This variant is not predicted to affect splicing (SpliceAI score 0.01) (BP4), and in a mini-gene assay, no effect of this variant on splicing was observed (PMID: 25312915; BP7_Strong_RNA). This variant has been reported with a second DYSF variant in at least two patients with a phenotype consistent with LGMD, but it was not considered a diagnostic finding in either case (PMID: 25591676, 34559919). In summary, this variant meets the criteria to be classified as Benign 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; 09/30/2025): BA1, BP4, BP7_Strong_RNA.

Met criteria codes

• BP7_Strong: In a mini-gene assay, this variant did not effect splicing (PMID: 25312915; BP7_Strong_RNA).
• BA1: The Grpmax FAF of this variant is 0.004287 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 216/44886 East Asian alleles), which is greater than the ClinGen LGMD VCEP threshold for BA1 (>0.003), meeting this criterion (BA1).
• BS3: This variant demonstrates by mini gene assay no significant splicing motif alteration detected. PMID 25312915. Direct quote from the paper: "No effect on splicing was observed for the mutation c.5767+6C>T in agreement with bioinformatics predictions provided by HSF."
• BP4: This variant is not predicted to affect splicing (SpliceAI score 0.01) (BP4). GENEie gives a 75% probability of being splice neutral. Per Walker et al. guidelines, BP4 can be co-applied with BP7_Strong_RNA. A B classification would also be reached if BP4 not applied.

Not Met criteria codes

• PP4: We do not consider PP4 if BA1/BS1 is applicable.
• PM3: This variant has been reported with a second DYSF variant in at least two patients with a phenotype consistent with LGMD, but it was not considered a diagnostic finding in either case (PMID: 25591676, 34559919). PMID: 25591676 Xi et al. (2014): F1‑323‑1‑1: c.5767+6C>T in unconfirmed phase with c.3116G>C (p.Arg1039Pro) (P in VCI). c.5767+6C>T was not considered a pathogenic variant by the authors. Normal gait but unable to run freely, hyperCKemia, negative IHC dysferlin protein staining and reduced dysferlin on western blot (11%). PMID: 34559919 Zhong et al. (2021): LOVD individual # 00376102: in unconfirmed phase with c.863A>Tp.(Asp288Val) (not in VCI but LP/P in ClinVar). The authors considered c.5767+6C>T a VUS, noting applicability of BS1, and considered the patient to have only a single presumed diagnostic variant. Unclear whether patient had reduced dysferlin expression and whether other LGMD genes were ruled out. We don't typically apply PP4 or PM3 if BS1 applies.