Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3PP4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1160G>C variant in DYSF, which is also known as NM_001130987.2: c.1256G>C p.(Arg419Pro), is a missense variant predicted to cause substitution of arginine to proline at amino acid 387, p.(Arg387Pro). This variant has been reported in three patients with LGMD (PMID:30564623, 39548682), including in an unknown phase with a pathogenic variant (c.2163-2A>G, 0.5 pts, PMID:30564623, LOVD Individual #00222090) and in a homozygous state in two individuals, both with known consanguinity (0.25 pts for each patient; PMID:39548682, LOVD Individuals #00392018, #00391975) (PM3; PP4). The highest minor allele frequency for this variant is 0.00002519 (1/39700 exome chromosomes) in the East Asian population in gnomAD v4.1.0, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance 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; 06/24/2025): PM2_Supporting, PM3, PP4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347213551/MONDO:0015152/180

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 7.98

Publications

2 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: Uncertain_significance. The variant received 5 ACMG points.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYSF	NM_001130987.2	MANE Select	c.1256G>C	p.Arg419Pro	missense	Exon 13 of 56	NP_001124459.1
DYSF	NM_003494.4	MANE Plus Clinical	c.1160G>C	p.Arg387Pro	missense	Exon 12 of 55	NP_003485.1
DYSF	NM_001130981.2		c.1253G>C	p.Arg418Pro	missense	Exon 13 of 56	NP_001124453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1256G>C	p.Arg419Pro	missense	Exon 13 of 56	ENSP00000386881.3
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1160G>C	p.Arg387Pro	missense	Exon 12 of 55	ENSP00000258104.3
DYSF	ENST00000409582.7	TSL:1	c.1253G>C	p.Arg418Pro	missense	Exon 13 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250886

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:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60386

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

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

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.0

PhyloP100

8.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.86

Sift

Uncertain

0.012

Sift4G

Uncertain

0.038

Polyphen

0.99

Vest4

0.84

MutPred

0.70

Loss of MoRF binding (P = 0.0761)

MVP

0.93

MPC

0.77

ClinPred

0.98

GERP RS

5.5

Varity_R

0.96

gMVP

0.94

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

chr2-71526326-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over