2-71659033-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3PM3PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4794G>T variant in DYSF, which is also known as NM_001130987.2: c.4911G>T (p.Lys1637Asn), is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 1598, p.(Lys1598Asn). This variant affects the last residue in exon 45 and is predicted to disrupt the consensus splice donor site (SpliceAI delta score 0.33) and strengthen an alternative splice site in the intron (SpliceAI delta score 0.63) (PP3). RNAseq analysis has demonstrated that this variant has a leaky splice effect, resulting in skipping of exon 43 and an inframe deletion, p.Gly1547_Lys1598del, in a subset of transcripts (PMID:36983702). This variant has been detected in nine individuals with features consistent with LGMD (PMID:33144682; 33610434; 30564623; 36983702; 27195159; ClinVar SCV005360734.1 internal data communication; LOVD DYSF_000170), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T, p.(Arg1586Ter), 1.0 pt, LOVD Individual #00215321; NM_003494.4: c.6124C>T p.(Arg2042Cys), 1.0 pt, ClinVar SCV005360734.1 internal data communication). In at least four patients, it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID:36983702); (NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts x2, PMID:36983702; PMID:30564623; LOVD Individual #00220316); (NM_003494.4: c.755C>T p.(Thr252Met), 0.5 pts, PMID:30564623; LOVD Individual #00219977) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF displayed a progressive limb girdle pattern of weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID:27195159). The filtering allele frequency of this variant is 0.0002 for gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 201/1112000 European (non-Finnish) chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (criterion not met). The Lys1598Asn protein was classified as functional in both 2A and ICC assays of dysferlin membrane localization (PMID:35028538), and the REVEL score is 0.387. 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; 06/24/2025): PP3, PM3_Very Strong, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222176/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic reviewed by expert panel P:9U:2O:1

Conservation

PhyloP100: 8.09

Publications

6 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 7 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

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 link	c.4911G>T	p.Lys1637Asn	missense_variant, splice_region_variant	Exon 44 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 link	c.4794G>T	p.Lys1598Asn	missense_variant, splice_region_variant	Exon 43 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.4911G>T	p.Lys1637Asn	missense_variant, splice_region_variant	Exon 44 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8 link	c.4794G>T	p.Lys1598Asn	missense_variant, splice_region_variant	Exon 43 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000597

AC:

AN:

251434

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000144

AC:

211

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000181

AC:

201

AN:

1112000

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

AF:

0.0000526

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.581

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Feb 20, 2024

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RNA studies demonstrate a damaging effect resulting in an in-frame skipping of exon 43 and a small proportion of protein with no critical domains or pathogenic variation (PMID: 36983702); Reported previously as a variant of uncertain significance and seen with a second paternally inherited variant (phase unknown) in a patient with progressive proximal bilateral leg weakness, elevated CK and aldolase levels, nonspecific myopathy on EMG and nerve conduction studies, and a diagnosis of dysferlinopathy (LGMD2B). Patient also harbored variants in two other genes that were not thought to be related to the phenotype (PMID: 27195159); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Chakravorty2021[PDF], 33144682, 33610434, 24438169, 27602406, 30564623, 36983702, 27195159, 39900102)

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Apr 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DYSF c.4794G>T (p.Lys1598Asn) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in multiple RNA products (Rufibach_2023). The variant allele was found at a frequency of 6e-05 in 251434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6e-05 vs 0.0031), allowing no conclusion about variant significance. c.4794G>T has been observed in individual(s) affected with dysferlinopathy, including limb-girdle muscular dystrophy and Miyoshi myopathy (Harris_2016, Swaika_2016, Nallamilli_2018, Klee_2021, Moore_2021). The LOVD database reports at-least one individual in whom the variant was confirmed to be in trans as a compound heterozygous genotype. The following publications have been ascertained in the context of this evaluation (PMID: 27602406, 33144682, 33610434, 30564623, 36983702, 27195159). ClinVar contains an entry for this variant (Variation ID: 94331). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jun 24, 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.4794G>T variant in DYSF, which is also known as NM_001130987.2: c.4911G>T (p.Lys1637Asn), is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 1598, p.(Lys1598Asn). This variant affects the last residue in exon 45 and is predicted to disrupt the consensus splice donor site (SpliceAI delta score 0.33) and strengthen an alternative splice site in the intron (SpliceAI delta score 0.63) (PP3). RNAseq analysis has demonstrated that this variant has a leaky splice effect, resulting in skipping of exon 43 and an inframe deletion, p.Gly1547_Lys1598del, in a subset of transcripts (PMID: 36983702). This variant has been detected in nine individuals with features consistent with LGMD (PMID: 33144682; 33610434; 30564623; 36983702; 27195159; ClinVar SCV005360734.1 internal data communication; LOVD DYSF_000170), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T, p.(Arg1586Ter), 1.0 pt, LOVD Individual #00215321; NM_003494.4: c.6124C>T p.(Arg2042Cys), 1.0 pt, ClinVar SCV005360734.1 internal data communication). In at least four patients, it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702); (NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts x2, PMID: 36983702; PMID: 30564623; LOVD Individual #00220316); (NM_003494.4: c.755C>T p.(Thr252Met), 0.5 pts, PMID: 30564623; LOVD Individual #00219977) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF displayed a progressive limb girdle pattern of weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID: 27195159). The filtering allele frequency of this variant is 0.0002 for gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 201/1112000 European (non-Finnish) chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (criterion not met). The Lys1598Asn protein was classified as functional in both 2A and ICC assays of dysferlin membrane localization (PMID: 35028538), and the REVEL score is 0.387. 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; 06/24/2025): PP3, PM3_Very Strong, PP4_Strong.

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Pathogenic:2

Mar 13, 2023

Jain Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant is rare with an allele frequency in gnomad of 0.0054%. This variant has been observed in individuals with dysferilnopathy (PMID: 36983702, 21520333, 27195159, 30564623). In the majority of the cases, this variant is seen in the heterozygous state in conjunction with another likely pathogenic or pathogenic DYSF variant and in one case it has been shown to be in trans with the pathogenic DYSF variant, Arg1586X (PMID: 21520333). RNAseq analysis showed that this variant causes a leaky splice site that leads to 26-30% of all transcripts and 60% of the allele with this variant having an inframe deletion of exon 43 (p.G1547_K1598del), which deletes part of C2F which leads to the loss of 6% of the dysferlin protein amino acid sequence (PMID: 36983702). The remaining 40% of the allele with this variant results in the replacement of lysine with asparagine (p.K1598N). The ACMG classification criteria are: PM2 moderate, PM3 strong, PM4 moderate, PP4 supporting. Based on the above data, this variant has been classified as Likely Pathogenic.

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1598 of the DYSF protein (p.Lys1598Asn). This variant also falls at the last nucleotide of exon 43, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141704244, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 21520333, 27195159, 30564623, 33610434, 36983702). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 94331). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 36983702). For these reasons, this variant has been classified as Pathogenic.

DYSF-related disorder

Pathogenic:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DYSF c.4794G>T variant is predicted to result in the amino acid substitution p.Lys1598Asn. This variant has been reported with a second DYSF variant in several individuals with features of DYSF-related disorders (Swaika et al. 2016. PubMed ID: 27195159; Table S7, Nallamilli et al. 2018. PubMed ID: 30564623; Table S1, Rufibach et al. 2023. PubMed ID: 36983702). Additionally, at PreventionGenetics, this variant has been reported in the compound heterozygous state with a pathogenic DYSF variant in an individual with muscular dystrophy (internal data). This variant resides at the last nucleotide of exon 43, and RNA sequencing analysis from blood monocytes and muscle tissue from patients harboring this variant demonstrated a leaky splicing impact that resulted in an in frame skipping of exon 43 in ~26-30% of the RNA transcript (Rufibach et al. 2023. PubMed ID: 36983702). This variant is reported in 0.010% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has conflicting interpretations, ranging from uncertain to pathogenic, in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/94331/). This variant is interpreted as likely pathogenic.

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

Pathogenic:1

Feb 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Miyoshi muscular dystrophy 1

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;.;D;.;.;.;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.0029

MutationAssessor

Benign

0.0

.;.;.;.;M;.;.;.;.;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.39

Sift

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T

Vest4

0.70

ClinPred

0.46

GERP RS

4.8

Varity_R

0.38

gMVP

0.63

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.63

Position offset: 45

DS_DL_spliceai

0.33

Position offset: 0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over