rs377735262

Variant summary

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

The NM_001130987.2(DYSF):c.1717C>T(p.Arg573Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,608,660 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R573Q) has been classified as Uncertain significance.

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 criteria provided, multiple submitters, no conflicts P:9

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 2-71551631-C-T is Pathogenic according to our data. Variant chr2-71551631-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 94278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71551631-C-T is described in Lovd as [Pathogenic]. Variant chr2-71551631-C-T is described in Lovd as [Pathogenic]. Variant chr2-71551631-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-71551631-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1717C>T	p.Arg573Trp	missense_variant	19/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.1663C>T	p.Arg555Trp	missense_variant	19/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.1717C>T	p.Arg573Trp	missense_variant	19/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1663C>T	p.Arg555Trp	missense_variant	19/55	1	NM_003494.4	A1	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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 27, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 17, 2017	- -

DYSF-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 17, 2023

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

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). 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%. 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

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

MutationTaster

Benign

1.0

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

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