NM_001130987.2:c.2550_2553delGACA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001130987.2(DYSF):c.2550_2553delGACA(p.Thr851SerfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 9.25

Publications

0 publications found

Variant links:

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

DYSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71564194-TACAG-T is Pathogenic according to our data. Variant chr2-71564194-TACAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 496872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYSF	NM_001130987.2	MANE Select	c.2550_2553delGACA	p.Thr851SerfsTer3	frameshift	Exon 24 of 56	NP_001124459.1
DYSF	NM_003494.4	MANE Plus Clinical	c.2496_2499delGACA	p.Thr833SerfsTer3	frameshift	Exon 24 of 55	NP_003485.1
DYSF	NM_001130981.2		c.2547_2550delGACA	p.Thr850SerfsTer3	frameshift	Exon 24 of 56	NP_001124453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.2550_2553delGACA	p.Thr851SerfsTer3	frameshift	Exon 24 of 56	ENSP00000386881.3
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.2496_2499delGACA	p.Thr833SerfsTer3	frameshift	Exon 24 of 55	ENSP00000258104.3
DYSF	ENST00000409582.7	TSL:1	c.2547_2550delGACA	p.Thr850SerfsTer3	frameshift	Exon 24 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251488

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Jul 29, 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.2496_2499del p.(Thr833SerfsTer3) variant in DYSF, which is also known as NM_001130987.2: c.2550_2553del p.(Thr851SerfsTer3), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 24/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least three patients with signs of LGMD, including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 21522182) and in unknown phase with a pathogenic variant (NM_003494.4: c.5668-7G>A, 0.5 pts, PMID: 36983702) (PM3). At least one patient with this variant had a second presumed diagnostic variant in DYSF and displayed progressive limb girdle muscle weakness and significantly reduced dysferlin expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong). The filtering allele frequency for this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1112012 European (non-Finnish) chromosomes), which is less than the ClinGen 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, PP4_Strong, PM2_Supporting.

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1

Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Apr 19, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Pathogenic:1

Nov 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Thr833Serfs*3) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs755849745, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy and/or Miyoshi myopathy (PMID: 17994539, 21522182). ClinVar contains an entry for this variant (Variation ID: 496872). For these reasons, this variant has been classified as Pathogenic.

Miyoshi muscular dystrophy 1

Pathogenic:1

Jun 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.3

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over