2-71598661-C-G

Variant names:

• chr2-71598661-C-G
• rs143393575
• NM_001130987.2:c.3672C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PM2_Supporting PM3_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3618C>G p.(Tyr1206Ter) variant in DYSF, which is also known as NM_001130987.2: c.3672C>G p.(Tyr1224Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 33/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with features of LGMD, including in a homozygous state without reported familial consanguinity in one patient (0.5 pts, PMID:30564623, LOVD Individual #00219431) and in unknown phase or confirmed in trans with a second presumed diagnostic DYSF variant in at least one patient (NM_003494.4: c.4439A>C p.(Lys1480Thr), PMID:15827562, 30919934, LOVD Individual #00215274) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness (PMID:30919934; PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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; 05/28/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347224046/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -2.29
• Publications: 0 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 11 ACMG points.

• PVS1: 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.
• 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.3672C>G	p.Tyr1224*	stop_gained	Exon 33 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3618C>G	p.Tyr1206*	stop_gained	Exon 33 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3672C>G	p.Tyr1224*	stop_gained	Exon 33 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.3618C>G	p.Tyr1206*	stop_gained	Exon 33 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

May 28, 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.3618C>G p.(Tyr1206Ter) variant in DYSF, which is also known as NM_001130987.2: c.3672C>G p.(Tyr1224Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 33/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with features of LGMD, including in a homozygous state without reported familial consanguinity in one patient (0.5 pts, PMID: 30564623, LOVD Individual #00219431) and in unknown phase or confirmed in trans with a second presumed diagnostic DYSF variant in at least one patient (NM_003494.4: c.4439A>C p.(Lys1480Thr), PMID: 15827562, 30919934, LOVD Individual #00215274) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness (PMID: 30919934; PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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; 05/28/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. -

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

Apr 02, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Jul 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.21	N
PhyloP100		-2.3
Vest4		0.93
GERP RS		-9.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143393575; hg19: chr2-71825791;