rs377735262

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3PP1PS3_ModeratePM3_StrongPP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID:16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID:25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID:19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID:25591676) (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:16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID:25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp 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 exceeds the 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; 01/08/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222133/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 0.553

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.

PM3

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

PP1

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.1717C>T	p.Arg573Trp	missense_variant	Exon 19 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.1663C>T	p.Arg555Trp	missense_variant	Exon 19 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.1717C>T	p.Arg573Trp	missense_variant	Exon 19 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.1663C>T	p.Arg555Trp	missense_variant	Exon 19 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000292

AC:

AN:

240060

Hom.:

AF XY:

0.0000310

AC XY:

AN XY:

129144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1456506

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

723760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000454

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000473

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000905

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Mar 08, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect on protein expression and localization (PMID: 35028538); 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: 25312915, 25591676, 19493611, 16010686, 22318734, 24488599, 19015158, 26579332, 23527661, 21522182, 34559919, 33927379, 27066573, 17698709, 36983702, 32400077, 33258288, 23519732, 25143362, 25591678, 31873062, 33610434, 18853459, 32664072, 32528171, 33715265, 31066050, 36672942, 22174839, 35028538) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:3

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1717C>T (p.Arg573Trp) variant in the DYSF gene has been observed in individual(s) with DYSF-related conditions (Izumi, Rumiko et al.,2015). This variant is reported with the allele frequency (0.003%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Arginine at position 573 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Arginine in DYSF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. However,functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Pathogenic. -

Jul 27, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID: 16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID: 25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID: 19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID: 25591676) (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: 16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID: 25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp 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 exceeds the 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; 01/08/2025): PM3_Strong, PP4_Strong, PP1, 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

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DYSF-related disorder

Pathogenic:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1663C>T (p.Arg555Trp) variant has been reported in at least six studies in a total of 10 patients with DYSF-related disorders, including three in a homozygous state and seven in a compound heterozygous state. The p.Arg555Trp variant was absent from 90 controls but is reported at a frequency of 0.00004 in the Total population of the Exome Aggregation Consortium. Functional studies using a myoblast cell line derived from a patient carrying the p.Arg555Trp variant and a second DYSF variant showed that the variant protein was degraded by proteasomes. Treatment with protease inhibitors rescued dysferlin expression and function. Based on the evidence, the p.Arg555Trp variant is classified as pathogenic for DYSF-related disorders. -

Miyoshi muscular dystrophy 1

Pathogenic:1

Jan 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Oct 23, 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 555 of the DYSF protein (p.Arg555Trp). This variant is present in population databases (rs377735262, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 17698709, 25591676, 27066573). ClinVar contains an entry for this variant (Variation ID: 94278). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DYSF function (PMID: 22174839). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

.;.;H;.;H;.;.;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.2

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

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

0.99

MVP

0.98

MPC

0.66

ClinPred

0.98

GERP RS

4.6

Varity_R

0.69

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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