rs398123807

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS3_ModeratePM3_StrongPP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.857T>A variant in DYSF, which is also known as NM_001130987.2: c.953T>A p.(Val318Glu), is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 318 p.(Val318Glu). This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID:18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID:33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID:18832576 (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:18832576). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID:36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant 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 0.95, which exceeds the LGMD 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): PM2_Supporting, PM3_Strong, PP4_Strong, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222220/MONDO:0015152/180

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

DYSF
NM_001130987.2 missense, splice_region

Scores

Splicing: ADA: 0.3869

Clinical Significance

Pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 6.96

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: Pathogenic. The variant received 12 ACMG points.

PS3

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

PM2

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

PM3

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.953T>A	p.Val318Glu	missense_variant, splice_region_variant	Exon 10 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.857T>A	p.Val286Glu	missense_variant, splice_region_variant	Exon 9 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.953T>A	p.Val318Glu	missense_variant, splice_region_variant	Exon 10 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.857T>A	p.Val286Glu	missense_variant, splice_region_variant	Exon 9 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251494

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111976

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Aug 03, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DYSF c.857T>A (p.Val286Glu) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Althought the variant alters the second nucleotide of exon 9 near the 3' splice acceptor junction, computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes. c.857T>A has been reported in the literature in compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive 2B or dysferlinopathy (e.g. Dominov_2014, Harris_2016, Charnay_2021, Kesari_2021, Moore_2021) or in an individual with undiagnosed limb-girdle weakness with unspecified variant zygosity (e.g. Topf_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24488599, 33927379, 25493284, 27602406, 18832576, 33610434, 32528171). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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.857T>A variant in DYSF, which is also known as NM_001130987.2: c.953T>A p.(Val318Glu), is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 318 p.(Val318Glu). This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID: 18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID: 33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID: 18832576 (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID: 36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant 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 0.95, which exceeds the LGMD 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): PM2_Supporting, PM3_Strong, PP4_Strong, PS3_Moderate, PP3. -

not provided

Pathogenic:1Uncertain:1

Jan 13, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2012

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the DYSF protein (p.Val286Glu). This variant is present in population databases (rs398123807, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18832576, 25493284, 32528171, 33610434, 33927379). ClinVar contains an entry for this variant (Variation ID: 94365). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:1

Jun 05, 2024

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

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

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

.;.;M;.;M;.;.;.;.;.;.

PhyloP100

7.0

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

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

0.98

MutPred

0.86

.;.;Gain of disorder (P = 0.0361);.;Gain of disorder (P = 0.0361);.;.;.;.;.;.;

MVP

0.98

MPC

0.83

ClinPred

0.99

GERP RS

4.6

Varity_R

0.93

gMVP

0.93

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.39

dbscSNV1_RF

Benign

0.40

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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