rs727503909

Variant names:

• chr2-71568304-TG-T
• rs727503909
• NM_001130987.2:c.2833delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4 PP1 PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2779del p.(Ala927LeufsTer21) variant in DYSF, which is also known as NM_001130987.2: c.2833del p.(Ala945LeufsTer21), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 27/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 13 individuals with limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (c.857T>A (p.Val286Glu), 1.0 pt, PMID:18832576), and 10 were homozygous (0.75 pts, PMID:16010686, 17825554) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:18832576, 17825554). The variant was also reported to co-segregate with the disease in 10 affected family members and has been described as a founder variant among Jews of the Caucus region, with an estimated carrier frequency of 4% (PP1 (capped with PP4_Strong); PMID:17825554). The filtering allele frequency of the variant is 0.0006 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 4/15288), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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; 01/08/2025): PVS1, PM3, PP4_Strong, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA233930/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DYSF NM_001130987.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1
• Conservation: PhyloP100: 9.76

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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.2833delG	p.Ala945LeufsTer21	frameshift_variant	Exon 26 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2779delG	p.Ala927LeufsTer21	frameshift_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.2833delG	p.Ala945LeufsTer21	frameshift_variant	Exon 26 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.2779delG	p.Ala927LeufsTer21	frameshift_variant	Exon 26 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250996 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

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: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461888 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

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: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Jun 19, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID:25821721, 22194990, 19084402, 16010686, 18853459, 17825554). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Dec 28, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2779delG pathogenic variant in the DYSF gene has been previously reported multiple times in association with DYSF-related disorders when present in the homozygous state or when in trans with another pathogenic DYSF variant (Krahn et al., 2009; Paradas et al., 2009; Ceyhan-Birsoy et al., 2015). This variant is observed in 7/34,416 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The c.2779delG variant causes a frameshift starting with codon Alanine 927, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Ala927LeufsX21. This variant is predicted to cause loss of normal protein function either through protein truncation of nonsense-mediated mRNA decay. -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: PVS1, PM2, PM3, PS4:Supporting -

Miyoshi muscular dystrophy 1 Pathogenic:3 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Jews of the Caucasus -

May 06, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2018

Genetic Diseases Diagnostic Center, Koc University Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.2779del p.(Ala927LeufsTer21) variant in DYSF, which is also known as NM_001130987.2: c.2833del p.(Ala945LeufsTer21), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 27/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 13 individuals with limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (c.857T>A (p.Val286Glu), 1.0 pt, PMID: 18832576), and 10 were homozygous (0.75 pts, PMID: 16010686, 17825554) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576, 17825554). The variant was also reported to co-segregate with the disease in 10 affected family members and has been described as a founder variant among Jews of the Caucus region, with an estimated carrier frequency of 4% (PP1 (capped with PP4_Strong); PMID: 17825554). The filtering allele frequency of the variant is 0.0006 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 4/15288), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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; 01/08/2025): PVS1, PM3, PP4_Strong, PP1. -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala927Leufs*21) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs745407251, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy or pseudometabolic muscular dystrophy (PMID: 16010686, 17825554, 18832576, 18853459, 19084402, 22194990, 25821721). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6685). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs727503909; hg19: chr2-71795434;