rs150877497

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS3_ModeratePM3_StrongPP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3113G>A variant in DYSF, which is also known as NM_001130987.2: c.3167G>A (p.Arg1056Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1038, p.(Arg1038Gln). This variant has been detected in at least seven patients with features consistent with LGMD (PMID:36983702, 26404900, 34559919, 14678801, 30919934, 27854218, 21522182), including in a homozygous state (0.5 pts, PMID:30919934) and confirmed in trans (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID:27854218) and in unknown phase (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.25 pts, PMID:14678801, 26404900; NM_003494.4: c.2077delC p.(His693ThrfsTer4), 0.25 pts, PMID:21522182) with a variant classified as at least likely pathogenic (PM3_Strong). At least one patient with this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:36983702, 14678801, 21522182). The filtering allele frequency of this variant is 0.000056915 (the upper threshold of the 95% CI of 50/1111952 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Gln protein did not reach the cell membrane, indicating an impact on protein function (PMID:35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). 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; 02/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1706448/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15U:2

Conservation

PhyloP100: 9.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

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.

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.3167G>A	p.Arg1056Gln	missense_variant	Exon 29 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.3113G>A	p.Arg1038Gln	missense_variant	Exon 29 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.3167G>A	p.Arg1056Gln	missense_variant	Exon 29 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.3113G>A	p.Arg1038Gln	missense_variant	Exon 29 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

250678

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000970

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000473

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Dec 07, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 03, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing at GeneDx and in the published literature (Cagliani et al., 2003; Krahn et al., 2009). Western blot analysis and immunohistochemistry demonstrated individuals harboring R1038Q had reduced dysferlin (Cagliani et al., 2003; Xi et al., 2014; Nagaraju et al., 2008). The R1038Q variant is observed in 11/111,482 (0.01%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R1038Q as a pathogenic variant. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:4

Feb 23, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242418). A different missense change at the same codon (p.Arg1056Pro) has been reported to be associated with DYSF related disorder (PMID: 33610434). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 02, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:18276788). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18276788) (PMID:14678801). -

Aug 12, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Distal myopathy with anterior tibial onset

Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Mar 21, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state. -

Qualitative or quantitative defects of dysferlin

Pathogenic:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 13, 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 glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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%. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Feb 25, 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.3113G>A variant in DYSF, which is also known as NM_001130987.2: c.3167G>A (p.Arg1056Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1038, p.(Arg1038Gln). This variant has been detected in at least seven patients with features consistent with LGMD (PMID: 36983702, 26404900, 34559919, 14678801, 30919934, 27854218, 21522182), including in a homozygous state (0.5 pts, PMID: 30919934) and confirmed in trans (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 27854218) and in unknown phase (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.25 pts, PMID: 14678801, 26404900; NM_003494.4: c.2077delC p.(His693ThrfsTer4), 0.25 pts, PMID: 21522182) with a variant classified as at least likely pathogenic (PM3_Strong). At least one patient with this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 14678801, 21522182). The filtering allele frequency of this variant is 0.000056915 (the upper threshold of the 95% CI of 50/1111952 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Gln protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). 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; 02/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. -

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

Pathogenic:1

Apr 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

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

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.88

MVP

0.98

MPC

0.69

ClinPred

0.98

GERP RS

5.1

Varity_R

0.73

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over