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 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.2865-2A>C

CA10606168

288644 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
UUID: 64dfdeb5-7855-4694-ada1-d6de69c4b845
Approved on: 2025-01-08
Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.2865-2A>C
NM_001130987.2(DYSF):c.2865-2A>C
NC_000002.12:g.71569818A>C
CM000664.2:g.71569818A>C
NC_000002.11:g.71796948A>C
CM000664.1:g.71796948A>C
NC_000002.10:g.71650456A>C
NG_008694.1:g.121196A>C
ENST00000698057.1:c.237-2A>C
ENST00000258104.8:c.2811-2A>C
ENST00000410020.8:c.2865-2A>C
ENST00000258104.7:c.2811-2A>C
ENST00000394120.6:c.2814-2A>C
ENST00000409366.5:c.2814-2A>C
ENST00000409582.7:c.2862-2A>C
ENST00000409651.5:c.2907-2A>C
ENST00000409744.5:c.2772-2A>C
ENST00000409762.5:c.2862-2A>C
ENST00000410020.7:c.2865-2A>C
ENST00000410041.1:c.2865-2A>C
ENST00000413539.6:c.2904-2A>C
ENST00000429174.6:c.2811-2A>C
NM_001130455.1:c.2814-2A>C
NM_001130976.1:c.2769-2A>C
NM_001130977.1:c.2769-2A>C
NM_001130978.1:c.2811-2A>C
NM_001130979.1:c.2904-2A>C
NM_001130980.1:c.2862-2A>C
NM_001130981.1:c.2862-2A>C
NM_001130982.1:c.2907-2A>C
NM_001130983.1:c.2814-2A>C
NM_001130984.1:c.2772-2A>C
NM_001130985.1:c.2865-2A>C
NM_001130986.1:c.2772-2A>C
NM_001130987.1:c.2865-2A>C
NM_003494.3:c.2811-2A>C
NM_001130455.2:c.2814-2A>C
NM_001130976.2:c.2769-2A>C
NM_001130977.2:c.2769-2A>C
NM_001130978.2:c.2811-2A>C
NM_001130979.2:c.2904-2A>C
NM_001130980.2:c.2862-2A>C
NM_001130981.2:c.2862-2A>C
NM_001130982.2:c.2907-2A>C
NM_001130983.2:c.2814-2A>C
NM_001130984.2:c.2772-2A>C
NM_001130985.2:c.2865-2A>C
NM_001130986.2:c.2772-2A>C
NM_003494.4:c.2811-2A>C
More

Pathogenic

Met criteria codes 5
PP4_Strong PM3_Strong PP1 PVS1 PM2_Supporting
Not Met criteria codes 21
PS1 PS2 PS3 PS4 BP4 BP3 BP1 BP2 BP5 BP7 PP2 PP3 PM6 PM1 PM5 PM4 BA1 BS2 BS1 BS4 BS3

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.2811-2A>C variant in DYSF, which is also known as NM_001130987.2: c.2865-2A>C, occurs within the canonical splice acceptor site of intron 26. It is predicted to cause skipping of biologically relevant exon 27/55, resulting in a frameshift and introduction of a premature truncation codon that is expected to lead to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. RNAseq analysis has shown that this variant results in near-complete elimination of normal splicing, resulting in the production of three alternative transcripts with a frameshift and premature truncation (PMID: 36983702) (PVS1_RNA). This variant has been detected in at least 4 unrelated individuals with dysferlinopathy (PMID: 36983702, 26671124, 33927379, 30564623). Of those individuals, two were homozygous (1.0 pt), one was compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.1852G>A p.Gly618Arg, 1.0 pt), and one carried a variant classified as at least likely pathogenic in unknown phase (c.5529G>A p.Trp1843Ter, 0.25 pts) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702). The variant has also been reported to segregate with LGMD in two affected family members from one family (PMID: 26671124; PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/08/2025): PVS1_RNA, PP4_Strong, PM3_Strong, PP1, PM2_Supporting.
Met criteria codes
PP4_Strong
At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and blood monocytes, which is specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702).
PM3_Strong
This variant has been detected in at least 4 unrelated individuals with dysferlinopathy (PMID: 36983702, 26671124, 33927379, 30564623). Of those individuals, two were homozygous (1.0 pt), one was compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.1852G>A p.Gly618Arg, 1.0 pt), and one carried a variant classified as at least likely pathogenic in unknown phase (c.5529G>A p.Trp1843Ter, 0.25 pts) (PM3_Strong).
PP1
The variant has been reported to segregate with LGMD in 2 affected family members from 1 family (PP1; PMID: 26671124).
PVS1
The NM_001130987.2: c.2865-2A>C variant in DYSF, which is also known as NM_003494.4: c.2811-2A>C, occurs within the canonical splice acceptor site (+/- 1,2) of intron 26 (NM_003494.4). It is predicted to cause skipping of biologically relevant exon 27/55 (NM_003494.4), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). RNAseq analysis has shown that this variant results in near-complete elimination of normal splicing, resulting in the production of three alternative transcripts with a frameshift and premature truncation (PMID: 36983702) (PVS1_RNA).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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