2-71570680-G-C

Variant names:

• chr2-71570680-G-C
• rs150877497
• NM_001130987.2:c.3167G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PS3_Moderate PM2_Supporting PM5 PM3 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3113G>C variant in DYSF, which is also known as NM_001130987.2: c.3167G>C p.(Arg1056Pro), is a missense variant predicted to cause substitution of arginine by proline at amino acid 1038, p.(Arg1038Pro). This variant has been reported in at least one individual with features consistent with LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pt, PMID:36983702, 33610434) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:33610434; 36983702). The filtering allele frequency of this variant is 0.000014124 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 9/1111952 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID:35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.89, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Another missense variant at the same codon, c.3113G>A p.(Arg1038Gln), has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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; 04/16/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347217058/MONDO:0015152/180

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.76
• Publications: 15 publications found

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

ACMG classification

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.
• PM5: 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.3167G>C	p.Arg1056Pro	missense_variant	Exon 29 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3113G>C	p.Arg1038Pro	missense_variant	Exon 29 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3167G>C	p.Arg1056Pro	missense_variant	Exon 29 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.3113G>C	p.Arg1038Pro	missense_variant	Exon 29 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250678 AF XY: 0.00000737

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Apr 16, 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.3113G>C variant in DYSF, which is also known as NM_001130987.2: c.3167G>C p.(Arg1056Pro), is a missense variant predicted to cause substitution of arginine by proline at amino acid 1038, p.(Arg1038Pro). This variant has been reported in at least one individual with features consistent with LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pt, PMID: 36983702, 33610434) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 33610434; 36983702). The filtering allele frequency of this variant is 0.000014124 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 9/1111952 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.89, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Another missense variant at the same codon, c.3113G>A p.(Arg1038Gln), has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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; 04/16/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5. -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Pathogenic:1

Jan 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1038 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 33610434). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1038 of the DYSF protein (p.Arg1038Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;M;.;.;.;.;.;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	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		0.92
MutPred		0.61		.;.;Gain of glycosylation at R1038 (P = 0.0192);.;Gain of glycosylation at R1038 (P = 0.0192);.;.;.;.;.;.;
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.90
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs150877497; hg19: chr2-71797810;