rs398123797

Positions:

• chr2-71679123-ACCAG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP4_Strong PM3_Supporting PVS1 PP1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19) variant in DYSF, which is also known as NM_001130987.2: c.5953_5956del p.(Gln1985TrpfsTer19)), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 52/55, 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 3 unrelated individuals with limb girdle muscular dystrophy (PMID:30564623, 19528035), including in unknown phase with a pathogenic variant (c.1852G>C p.(Gly618Arg), 0.5 pt, PMID:30564623) (PM3_Supporting). 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:19528035, 30564623). The variant was also reported to co-segregate with the disease in one affected family member (PMID:19528035) (PP1). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), 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_Supporting, PP4_Strong, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222196/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: DYSF NM_001130987.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 3.54

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 14 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/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5953_5956delCAGC	p.Gln1985fs	frameshift_variant	53/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5836_5839delCAGC	p.Gln1946fs	frameshift_variant	52/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5953_5956delCAGC	p.Gln1985fs	frameshift_variant	53/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.5836_5839delCAGC	p.Gln1946fs	frameshift_variant	52/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461770 Hom.: 0 AF XY: 0.0000289 AC XY: 21 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000315

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 28, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 12, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2016	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 08, 2025

The NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19) variant in DYSF, which is also known as NM_001130987.2: c.5953_5956del p.(Gln1985TrpfsTer19)), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 52/55, 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 3 unrelated individuals with limb girdle muscular dystrophy (PMID: 30564623, 19528035), including in unknown phase with a pathogenic variant (c.1852G>C p.(Gly618Arg), 0.5 pt, PMID: 30564623) (PM3_Supporting). 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: 19528035, 30564623). The variant was also reported to co-segregate with the disease in one affected family member (PMID: 19528035) (PP1). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), 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_Supporting, PP4_Strong, PP1. -

DYSF-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2023

The DYSF c.5836_5839delCAGC variant is predicted to result in a frameshift and premature protein termination (p.Gln1946Trpfs*19). This variant was reported in individuals with DYSF-related muscular dystrophy (Rosales et al 2010. PubMed ID: 20544924; Klinge et al 2009. PubMed ID: 19528035; Moore et al 2021. PubMed ID: 33610434; Nilsson et al 2013. PubMed ID: 23519732). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71906253-ACCAG-A). Frameshift variants in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2024

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change creates a premature translational stop signal (p.Gln1946Trpfs*19) 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 (rs398123797, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy (PMID: 20544924, 23519732). ClinVar contains an entry for this variant (Variation ID: 94347). 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)		0.010		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: rs398123797; hg19: chr2-71906253;