rs202218890

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001130987.2(DYSF):c.2929C>T(p.Arg977Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,974 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.33

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 2-71569884-C-T is Pathogenic according to our data. Variant chr2-71569884-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71569884-C-T is described in Lovd as [Pathogenic]. Variant chr2-71569884-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-71569884-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.2929C>T	p.Arg977Trp	missense_variant	Exon 27 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.2875C>T	p.Arg959Trp	missense_variant	Exon 27 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.2929C>T	p.Arg977Trp	missense_variant	Exon 27 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.2875C>T	p.Arg959Trp	missense_variant	Exon 27 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

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:

0.000193

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:

0.0000398

AC:

AN:

251350

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135852

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000336

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM2, PP1, PP4 -

Nov 10, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19528035, 26806107, 22194990, 14678801, 17994539, 16100712, 21522182, 17070050, 30028523, 31130284, 34426522, 31589614, 33258288, 32528171, 33715265, 33610434, 35175440, 34559919, 24438169) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:3

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 04, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DYSF-related disorder

Pathogenic:1

Oct 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DYSF c.2875C>T variant is predicted to result in the amino acid substitution p.Arg959Trp. This variant has been repeatedly reported in individuals with autosomal recessive dysferlinopathy; immunohistochemistry assays for these patients have demonstrated severely reduced to an absence of dysferlin protein expression (see Cagliani et al. 2003. PubMed ID: 14678801; Klinge et al. 2009. PubMed ID: 19528035; Gallardo et al. 2011. PubMed ID: 22194990; Arrigoni et al. 2018. PubMed ID: 30028523; Fanin et al. 2006. PubMed ID: 16934466; Guglieri et al. 2008. PubMed ID: 17994539; De Luna et al. 2006. PubMed ID: 17070050). This variant is reported in 0.0070% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71797014-C-T). Taken together, this variant is interpreted as pathogenic. -

Miyoshi muscular dystrophy 1

Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

May 02, 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 959 of the DYSF protein (p.Arg959Trp). This variant is present in population databases (rs202218890, gnomAD 0.006%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and Myoshi myopathy (PMID: 14678801, 16934466, 17070050, 19528035, 21522182, 22194990). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 284254). 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 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.4

.;.;L;.;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

0.95

MutPred

0.89

.;.;Loss of disorder (P = 0.0562);.;Loss of disorder (P = 0.0562);.;.;.;.;.;.;

MVP

0.93

MPC

0.66

ClinPred

0.93

GERP RS

5.2

Varity_R

0.91

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