rs760443264

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001130987.2(DYSF):c.3169C>T(p.Arg1057Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1057Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 1.12

Publications

10 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001130987.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-71570683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1491619.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 2-71570682-C-T is Pathogenic according to our data. Variant chr2-71570682-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282449.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.3169C>T	p.Arg1057Trp	missense_variant	Exon 29 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 link	c.3115C>T	p.Arg1039Trp	missense_variant	Exon 29 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.3169C>T	p.Arg1057Trp	missense_variant	Exon 29 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8 link	c.3115C>T	p.Arg1039Trp	missense_variant	Exon 29 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

250656

AF XY:

0.0000221

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:

0.0000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000351

AC:

AN:

1111948

Other (OTH)

AF:

0.0000166

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.0000565

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Aug 17, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2025

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 22, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 24438169, 32419263, 34559919, 27647186, 31268554, 17070050, 33610434)

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:2

Feb 02, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 11, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

DYSF-related disorder

Pathogenic:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DYSF c.3115C>T variant is predicted to result in the amino acid substitution p.Arg1039Trp. This variant has been reported in individuals with limb girdle muscular dystrophy (Jin et al. 2016. PubMed ID: 27647186; Winckler et al. 2019. PubMed ID: 31268554; Table S1, Zhong et al. 2021. PubMed ID: 34559919). Alternate substitutions of the adjacent amino acid residue (p.Arg1038Gln and p.Arg1038Pro) have been reported in individuals with limb girdle muscular dystrophy (Cagliani et al. 2003. PubMed ID: 14678801; Table S1, Moore et al. 2021. PubMed ID: 33610434). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic.

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Pathogenic:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1039 of the DYSF protein (p.Arg1039Trp). This variant is present in population databases (rs760443264, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of dysferlinopathy and/or DYSF-related conditions (PMID: 27647186, 31268554). ClinVar contains an entry for this variant (Variation ID: 282449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1039 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17070050; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Miyoshi muscular dystrophy 1

Pathogenic:1

Jan 16, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

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

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.075

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

0.0

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

PhyloP100

1.1

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.3

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

Sift

Benign

0.055

T;D;T;D;T;D;D;D;T;D;T

Sift4G

Pathogenic

0.0

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

Vest4

0.81

ClinPred

0.95

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.85

Mutation Taster

=1/99

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over