rs727503910

Variant names:

• chr2-71568318-G-C
• rs727503910
• NM_001130987.2:c.2844G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-71568318-G-C
• chr2-71568318-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PS3_Moderate PM2_Supporting PM3 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2790G>C variant in DYSF, which is also known as NM_001130987.2: c.2844G>C p.(Trp948Cys), is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 930, p.(Trp930Cys). This variant has been detected in at least three individuals with LGMD (PMID:18853459, 36983702, 27602406), including confirmed in trans with a pathogenic variant (NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID:18853459, LOVD Individual #00215573) and in unknown phase with a pathogenic variant (NM_003494.4: c.2643+1G>A, 0.5 pts, PMID:36983702) (PM3). Although both patients were reported to have additional DYSF variants in unknown phase, these other variants could be classified as likely benign. At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:36983702, 18853459). This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Trp930Cys 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 0.87, which is above 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; 03/06/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA233931/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: 7.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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	c.2844G>C	p.Trp948Cys	missense_variant	Exon 26 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2790G>C	p.Trp930Cys	missense_variant	Exon 26 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.2844G>C	p.Trp948Cys	missense_variant	Exon 26 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.2790G>C	p.Trp930Cys	missense_variant	Exon 26 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

Mar 06, 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.2790G>C variant in DYSF, which is also known as NM_001130987.2: c.2844G>C p.(Trp948Cys), is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 930, p.(Trp930Cys). This variant has been detected in at least three individuals with LGMD (PMID: 18853459, 36983702, 27602406), including confirmed in trans with a pathogenic variant (NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 18853459, LOVD Individual #00215573) and in unknown phase with a pathogenic variant (NM_003494.4: c.2643+1G>A, 0.5 pts, PMID: 36983702) (PM3). Although both patients were reported to have additional DYSF variants in unknown phase, these other variants could be classified as likely benign. At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 18853459). This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Trp930Cys 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 0.87, which is above 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; 03/06/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. -

Nov 22, 2024

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.2790G>C (p.Trp930Cys) results in a non-conservative amino acid change located in the Dysferlin domain, N-terminal region (IPR006614) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250552 control chromosomes. c.2790G>C has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy and Dysferlinopathy (example, Krahn_2009, Moore_2021, Rufibach_2023, Therrien_2006). 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: 18853459, 33610434, 36983702, 16996541). ClinVar contains an entry for this variant (Variation ID: 167021). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Qualitative or quantitative defects of dysferlin Pathogenic:2

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 930 of the DYSF protein (p.Trp930Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18853459, 33610434). ClinVar contains an entry for this variant (Variation ID: 167021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mar 13, 2023

Jain Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant is absent from gnomAD v2.1.1. This variant has been reported in individuals with a clinical phenotype consistent with dysferlinopathy, associated with disease range dysferlin protein levels, and found in the heterozygous state in conjuction with the pathogeic or likely pathogenic DYSF variants, c.2643+1G>A, c.4024C>T, or c.3832C>T (PMID: 36983702, 18853459). This variant has also been reported to cause reduced dysferlin protein expression and no plasma membrane localization via an in vitro assay (PMID: 35028538). Both the REVEL (0.867) and CADD (25.7) scores support a deleterious effect. The ACMG classification criteria applied are: PM2 moderate, PM3 moderate, PP3, PP4 moderate, and PS3 supporting. Based on the above data, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Feb 05, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Oct 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1

Aug 03, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	.;.;M;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-12	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	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		0.92		.;.;Loss of sheet (P = 0.0084);.;Loss of sheet (P = 0.0084);.;.;.;.;.;.;
MVP		0.93
MPC		0.82
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs727503910; hg19: chr2-71795448;