NM_001130987.2:c.605C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID:16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign 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): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147766/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.0097 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 134 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:14

Conservation

PhyloP100: 1.39

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 Benign. Variant got -8 ACMG points.

BA1

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.605C>A	p.Ala202Glu	missense_variant	Exon 7 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.509C>A	p.Ala170Glu	missense_variant	Exon 6 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.605C>A	p.Ala202Glu	missense_variant	Exon 7 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.509C>A	p.Ala170Glu	missense_variant	Exon 6 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00967

AC:

1472

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00894

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0101

AC:

2546

AN:

251252

Hom.:

AF XY:

0.0102

AC XY:

1380

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00372

Gnomad FIN exome

AF:

0.00776

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0124

AC:

18138

AN:

1461844

Hom.:

134

Cov.:

AF XY:

0.0121

AC XY:

8810

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.00680

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00336

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00966

AC:

1471

AN:

152286

Hom.:

Cov.:

AF XY:

0.00901

AC XY:

671

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00894

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.00943

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.00977

AC:

1186

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala202Glu in exon 7 of DYSF: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (132/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34999029). -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 11, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BP4, BS1, BS2 -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_003494.4: c.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID: 16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign 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): BA1. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.23

.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.85

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

MetaRNN

Benign

0.0052

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

.;.;N;.;N;.;.;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.70

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0030

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.30

MPC

0.17

ClinPred

0.016

GERP RS

3.5

Varity_R

0.057

gMVP

0.19

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