NM_001130987.2:c.4911G>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001130987.2(DYSF):c.4911G>T(p.Lys1637Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2O:1

Conservation

PhyloP100: 8.09

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain C2 6 (size 118) in uniprot entity DYSF_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_001130987.2

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-71659033-G-T is Pathogenic according to our data. Variant chr2-71659033-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94331.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=2, Pathogenic=1, not_provided=1}. Variant chr2-71659033-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.4911G>T	p.Lys1637Asn	missense_variant, splice_region_variant	Exon 44 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.4794G>T	p.Lys1598Asn	missense_variant, splice_region_variant	Exon 43 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.4911G>T	p.Lys1637Asn	missense_variant, splice_region_variant	Exon 44 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.4794G>T	p.Lys1598Asn	missense_variant, splice_region_variant	Exon 43 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152126

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251434

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000144

AC:

211

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Aug 04, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect resulting in an in-frame skipping of exon 43 and a small proportion of protein with no critical domains or pathogenic variation (PMID: 36983702); Reported previously as a variant of uncertain significance and seen with a second paternally inherited variant (phase unknown) in a patient with progressive proximal bilateral leg weakness, elevated CK and aldolase levels, nonspecific myopathy on EMG and nerve conduction studies, and a diagnosis of dysferlinopathy (LGMD2B). Patient also harbored variants in two other genes that were not thought to be related to the phenotype (PMID: 27195159); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Chakravorty2021[PDF], 33144682, 33610434, 24438169, 27602406, 30564623, 36983702, 27195159, 39900102) -

Qualitative or quantitative defects of dysferlin

Pathogenic:2

Mar 13, 2023

Jain Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant is rare with an allele frequency in gnomad of 0.0054%. This variant has been observed in individuals with dysferilnopathy (PMID: 36983702, 21520333, 27195159, 30564623). In the majority of the cases, this variant is seen in the heterozygous state in conjunction with another likely pathogenic or pathogenic DYSF variant and in one case it has been shown to be in trans with the pathogenic DYSF variant, Arg1586X (PMID: 21520333). RNAseq analysis showed that this variant causes a leaky splice site that leads to 26-30% of all transcripts and 60% of the allele with this variant having an inframe deletion of exon 43 (p.G1547_K1598del), which deletes part of C2F which leads to the loss of 6% of the dysferlin protein amino acid sequence (PMID: 36983702). The remaining 40% of the allele with this variant results in the replacement of lysine with asparagine (p.K1598N). The ACMG classification criteria are: PM2 moderate, PM3 strong, PM4 moderate, PP4 supporting. Based on the above data, this variant has been classified as Likely Pathogenic. -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1598 of the DYSF protein (p.Lys1598Asn). This variant also falls at the last nucleotide of exon 43, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141704244, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 21520333, 27195159, 30564623, 33610434, 36983702). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 94331). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 36983702). For these reasons, this variant has been classified as Pathogenic. -

DYSF-related disorder

Pathogenic:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DYSF c.4794G>T variant is predicted to result in the amino acid substitution p.Lys1598Asn. This variant has been reported with a second DYSF variant in several individuals with features of DYSF-related disorders (Swaika et al. 2016. PubMed ID: 27195159; Table S7, Nallamilli et al. 2018. PubMed ID: 30564623; Table S1, Rufibach et al. 2023. PubMed ID: 36983702). Additionally, at PreventionGenetics, this variant has been reported in the compound heterozygous state with a pathogenic DYSF variant in an individual with muscular dystrophy (internal data). This variant resides at the last nucleotide of exon 43, and RNA sequencing analysis from blood monocytes and muscle tissue from patients harboring this variant demonstrated a leaky splicing impact that resulted in an in frame skipping of exon 43 in ~26-30% of the RNA transcript (Rufibach et al. 2023. PubMed ID: 36983702). This variant is reported in 0.010% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has conflicting interpretations, ranging from uncertain to pathogenic, in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/94331/). This variant is interpreted as likely pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Apr 20, 2025

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.4794G>T (p.Lys1598Asn) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in multiple RNA products (Rufibach_2023). The variant allele was found at a frequency of 6e-05 in 251434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6e-05 vs 0.0031), allowing no conclusion about variant significance. c.4794G>T has been observed in individual(s) affected with dysferlinopathy, including limb-girdle muscular dystrophy and Miyoshi myopathy (Harris_2016, Swaika_2016, Nallamilli_2018, Klee_2021, Moore_2021). The LOVD database reports at-least one individual in whom the variant was confirmed to be in trans as a compound heterozygous genotype. The following publications have been ascertained in the context of this evaluation (PMID: 27602406, 33144682, 33610434, 30564623, 36983702, 27195159). ClinVar contains an entry for this variant (Variation ID: 94331). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1

Pathogenic:1

Feb 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

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

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.75

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

MetaSVM

Uncertain

0.0029

MutationAssessor

Uncertain

2.4

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

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.39

Sift

Benign

0.12

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

Sift4G

Benign

0.15

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

Polyphen

0.76

P;P;D;D;D;D;D;D;D;D;P

Vest4

0.70

MutPred

0.50

.;.;.;.;Loss of methylation at K1598 (P = 0.0011);.;.;.;.;.;.;

MVP

0.82

MPC

0.52

ClinPred

0.46

GERP RS

4.8

Varity_R

0.38

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.63

Position offset: 45

DS_DL_spliceai

0.33

Position offset: 0

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