rs886042578

Variant names:

• chr2-71644047-AT-A
• rs886042578
• NM_001130987.2:c.4614delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PP1 PM2_Supporting PM3_Strong PVS1 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4497del p.(Phe1499LeufsTer4) variant in DYSF, which is also known as NM_001130987.2: c.4614del p.(Phe1538LeufsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 41/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). In the literature, this variant has also been described as c.4870delT. This variant has been detected in at least eight unrelated individuals with limb girdle muscular dystrophy (PMID:23243261, 12796534, 17070050, 27647186, 26088049, 17614318). Among these individuals, it was identified in a homozygous state in three patients (1.0 pts, PMID:26088049, 17614318, 12796534) and in trans with a pathogenic variant in at least one patient (c.2643+1G>A, 1.0 pt, PMID:23243261) (PM3_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 (PP4_Strong, PMID:27647186, 17070050). The variant was also reported to co-segregate with the disease in three affected family members from one family (PMID:17614318) (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, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10604426/MONDO:0015152/180

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYSF NM_001130987.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.592
• Publications: 3 publications found

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

DYSF Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4614delT	p.Phe1538LeufsTer4	frameshift_variant	Exon 42 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4497delT	p.Phe1499LeufsTer4	frameshift_variant	Exon 41 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4614delT	p.Phe1538LeufsTer4	frameshift_variant	Exon 42 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4497delT	p.Phe1499LeufsTer4	frameshift_variant	Exon 41 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725378

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110744

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_003494.4: c.4497del p.(Phe1499LeufsTer4) variant in DYSF, which is also known as NM_001130987.2: c.4614del p.(Phe1538LeufsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 41/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). In the literature, this variant has also been described as c.4870delT. This variant has been detected in at least eight unrelated individuals with limb girdle muscular dystrophy (PMID: 23243261, 12796534, 17070050, 27647186, 26088049, 17614318). Among these individuals, it was identified in a homozygous state in three patients (1.0 pts, PMID: 26088049, 17614318, 12796534) and in trans with a pathogenic variant in at least one patient (c.2643+1G>A, 1.0 pt, PMID: 23243261) (PM3_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 (PP4_Strong, PMID: 27647186, 17070050). The variant was also reported to co-segregate with the disease in three affected family members from one family (PMID: 17614318) (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, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. -

not provided Pathogenic:1

Mar 04, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886042578; hg19: chr2-71871177;