2-71511865-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP2

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.401C>T variant in DYSF, which is also known as NM_001130987.2: c.404C>T p.(Pro135Leu), is a missense variant predicted to cause substitution of proline by leucine at amino acid 134, p.(Pro134Leu). This variant has been observed in two individuals with features consistent with LGMD (PMID:36983702; 23406536; 30564623; LOVD Individual #00222735); however, in both cases it was identified in cis with a null variant, including one classified as pathogenic by the ClinGen LGMD VCEP (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), PMID:36983702) (BP2; PP4 and PM3 not applicable). The filtering allele frequency of this variant is 0.0001865 in gnomAD v4.1.0 genomes (the upper threshold of the 95% CI of 3/41580 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2 not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID:35028538; BS3 not met). The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 for BP4 (criterion not met). In summary, this variant meets the criteria to be classified as Likely 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; 06/17/2025): BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1705344/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:2

Conservation

PhyloP100: 3.69

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuromuscular disease caused by qualitative or quantitative defects of dysferlin
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
autosomal recessive limb-girdle muscular dystrophy type 2B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
distal myopathy with anterior tibial onset
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy, Paradas type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Miyoshi myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP2

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.404C>T	p.Pro135Leu	missense_variant	Exon 5 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.401C>T	p.Pro134Leu	missense_variant	Exon 5 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.404C>T	p.Pro135Leu	missense_variant	Exon 5 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.401C>T	p.Pro134Leu	missense_variant	Exon 5 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

156876

AF XY:

0.0000242

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000330

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000786

AC:

AN:

1399366

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

690182

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000649

AC:

AN:

1078960

Other (OTH)

AF:

0.0000172

AC:

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000204

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 30, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DYSF: PM2, PM3, BP4 -

not specified

Uncertain:1

Feb 03, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DYSF c.401C>T (p.Pro134Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 156876 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.401C>T has been reported in the literature in one individual affected with dysferlinopathy (Walter_2013). The report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Sep 26, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jun 17, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_003494.4: c.401C>T variant in DYSF, which is also known as NM_001130987.2: c.404C>T p.(Pro135Leu), is a missense variant predicted to cause substitution of proline by leucine at amino acid 134, p.(Pro134Leu). This variant has been observed in two individuals with features consistent with LGMD (PMID: 36983702; 23406536; 30564623; LOVD Individual #00222735); however, in both cases it was identified in cis with a null variant, including one classified as pathogenic by the ClinGen LGMD VCEP (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), PMID: 36983702) (BP2; PP4 and PM3 not applicable). The filtering allele frequency of this variant is 0.0001865 in gnomAD v4.1.0 genomes (the upper threshold of the 95% CI of 3/41580 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2 not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 for BP4 (criterion not met). In summary, this variant meets the criteria to be classified as Likely 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; 06/17/2025): BP2. -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

0.068

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.1

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

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.15

Sift

Uncertain

0.0030

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

Sift4G

Benign

0.54

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

Polyphen

0.98

D;B;D;D;P;D;P;P;P;D;D

Vest4

0.33

MutPred

0.32

Loss of glycosylation at P134 (P = 0.0174);Loss of glycosylation at P134 (P = 0.0174);Loss of glycosylation at P134 (P = 0.0174);Loss of glycosylation at P134 (P = 0.0174);Loss of glycosylation at P134 (P = 0.0174);.;.;.;.;.;.;

MVP

0.80

MPC

0.15

ClinPred

0.34

GERP RS

4.6

Varity_R

0.11

gMVP

0.25

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over