rs140108514

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM3_StrongPVS1_ModeratePP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2643+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>A, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids. Skipping of exon 25 was confirmed by minigene assay and RNAseq (PMID 25312915, 36983702; PVS1_Moderate_RNA). This variant has been detected in at least eight unrelated individuals with LGMD (PMID:30564623, 36983702, 33927379, 23243261, 22246893, 18853459). Of these individuals, four were homozygous (1.0 pt), and four were compound heterozygous; in at least two cases, the variant was confirmed in trans with a pathogenic or likely pathogenic variant (c.1948delC p.(Leu650TyrfsTer6), 1.0 pt; c.4497delT p.(Phe1499LeufsTer4), 1.0 pt) (PM3_Strong). At least one of these patients displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID:36983702, 33927379). The filtering allele frequency for this variant is 0.001335 in gnomAD v2.1.1 African/African American genomes (the lower threshold of the 95% CI of 18/8708), which is higher than the LGMD VCEP threshold of 0.001 for BS1; however, this variant is a frequently observed variant among patients, and the VCEP opted not to apply this code (BS1 exception). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the threshold for the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. Although the population frequency of this variant provides benign evidence, the VCEP considers this not inconsistent with the final classification given the frequency at which it is observed in the patient population. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate_RNA, PS1, PM3_Strong, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222141/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 9.99

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 Pathogenic. Variant got 14 ACMG points.

PVS1

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

PS1

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

PM3

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.2697+1G>A		splice_donor_variant, intron_variant	Intron 25 of 55	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.2643+1G>A		splice_donor_variant, intron_variant	Intron 25 of 54	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.2697+1G>A		splice_donor_variant, intron_variant	Intron 25 of 55	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.2643+1G>A		splice_donor_variant, intron_variant	Intron 25 of 54	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251492

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000421

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00145

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jan 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Published minigene assays show that this canonical splice variant results in the skipping of exon 25, suggesting that it results in abnormal splicing (Kergourlay et al., 2014); This variant is associated with the following publications: (PMID: 22246893, 25525159, 23243261, 12796534, 11532985, 18853459, 29382405, 31980526, 31589614, 33610434, 24438169, 25312915) -

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of Miyoshi myopathy and limb girdle muscular dystrophy, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is also referred to as c.2697+1G>A and c.3016+1G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to cause exon skipping (PMID: 25312915). -

Aug 23, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PM3_very_strong, PS4_moderate, PVS1_moderate -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:3

Oct 02, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.2697+1G>A variant in DYSF was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.1706% (41/24026) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140108514). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The c.2697+1G>A variant in DYSF has been reported in 3 individuals with LGMD (PMID: 23243261). The presence of this variant in combination with reported pathogenic variants and in 2 individuals with LGMD increases the likelihood that the c.2697+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.2697+1G>A variant may impact protein function by causing abnormal splicing of Exon 25 (PMID: 25312915). However, these types of assays may not accurately represent biological function.This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an in-frame transcript deletion and abnormal or absent protein. Loss of function In the DYSF gene is an established disease mechanism in autosomal recessive LGMD. In summary, the clinical significance of the 2697+1G>A variant is pathogenic. ACMG/AMP Criteria applied: PVS1_Moderate, PS3, PM3_Strong (Richards 2015). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:2

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant classified as pathogenic in the context of dysferlinopathy. c.2643+1G>A has been observed in cases with relevant disease (PMID: 30564623, 12796534, 23243261, 27854218, 18832576, 24488599, 21816046). Functional assessments of this variant are available in the literature (PMID: 25312915). c.2643+1G>A has been observed in population frequency databases (gnomAD: AFR 0.13%). In summary, NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1

Pathogenic:2

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

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.2643+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>A, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids. Skipping of exon 25 was confirmed by minigene assay and RNAseq (PMID 25312915, 36983702; PVS1_Moderate_RNA). This variant has been detected in at least eight unrelated individuals with LGMD (PMID: 30564623, 36983702, 33927379, 23243261, 22246893, 18853459). Of these individuals, four were homozygous (1.0 pt), and four were compound heterozygous; in at least two cases, the variant was confirmed in trans with a pathogenic or likely pathogenic variant (c.1948delC p.(Leu650TyrfsTer6), 1.0 pt; c.4497delT p.(Phe1499LeufsTer4), 1.0 pt) (PM3_Strong). At least one of these patients displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 33927379). The filtering allele frequency for this variant is 0.001335 in gnomAD v2.1.1 African/African American genomes (the lower threshold of the 95% CI of 18/8708), which is higher than the LGMD VCEP threshold of 0.001 for BS1; however, this variant is a frequently observed variant among patients, and the VCEP opted not to apply this code (BS1 exception). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the threshold for the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. Although the population frequency of this variant provides benign evidence, the VCEP considers this not inconsistent with the final classification given the frequency at which it is observed in the patient population. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate_RNA, PS1, PM3_Strong, PP4_Strong. -

DYSF-related disorder

Pathogenic:1

Apr 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DYSF c.2643+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in patients diagnosed with limb-girdle muscular dystrophy type 2B (LGMD2B) or Miyoshi myopathy (Krahn et al. 2009. PubMed ID: 18853459; Takahashi et al. 2013. PubMed ID: 23243261). In a mini-gene assay, the c.2643+1G>A variant led to exon skipping (Kergourlay et al. 2014. PubMed ID: 25312915). This variant has been reported at an allele frequency of ~0.2% in an African population; in other ethnicities it is absent or reported less frequently (i.e. <0.01%) (http://gnomad.broadinstitute.org/variant/2-71795213-G-A). Variants that disrupt the consensus splice donor site in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 25 of the DYSF gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs140108514, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and Miyoshi myopathy (PMID: 12796534, 18853459, 21816046, 22246893, 23243261, 27854218). This variant is also known as G3016+1A and c.3016+1G>A. ClinVar contains an entry for this variant (Variation ID: 94291). Studies have shown that disruption of this splice site results in skipping of exon 25, but is expected to preserve the integrity of the reading-frame (PMID: 25312915). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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