rs886043964

Positions:

• chr2-71569818-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PP4_Strong PP1 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2811-2A>C variant in DYSF, which is also known as NM_001130987.2: c.2865-2A>C, occurs within the canonical splice acceptor site of intron 26. It is predicted to cause skipping of biologically relevant exon 27/55, resulting in a frameshift and introduction of a premature truncation codon that is expected to lead to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. RNAseq analysis has shown that this variant results in near-complete elimination of normal splicing, resulting in the production of three alternative transcripts with a frameshift and premature truncation (PMID:36983702) (PVS1_RNA). This variant has been detected in at least 4 unrelated individuals with dysferlinopathy (PMID:36983702, 26671124, 33927379, 30564623). Of those individuals, two were homozygous (1.0 pt), one was compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.1852G>A p.Gly618Arg, 1.0 pt), and one carried a variant classified as at least likely pathogenic in unknown phase (c.5529G>A p.Trp1843Ter, 0.25 pts) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID:36983702). The variant has also been reported to segregate with LGMD in two affected family members from one family (PMID:26671124; PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/08/2025): PVS1_RNA, PP4_Strong, PM3_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10606168/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.09

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 18 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.
• 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.2865-2A>C		splice_acceptor_variant, intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2811-2A>C		splice_acceptor_variant, intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.2865-2A>C		splice_acceptor_variant, intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.2811-2A>C		splice_acceptor_variant, intron_variant		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:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 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.2811-2A>C variant in DYSF, which is also known as NM_001130987.2: c.2865-2A>C, occurs within the canonical splice acceptor site of intron 26. It is predicted to cause skipping of biologically relevant exon 27/55, resulting in a frameshift and introduction of a premature truncation codon that is expected to lead to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. RNAseq analysis has shown that this variant results in near-complete elimination of normal splicing, resulting in the production of three alternative transcripts with a frameshift and premature truncation (PMID: 36983702) (PVS1_RNA). This variant has been detected in at least 4 unrelated individuals with dysferlinopathy (PMID: 36983702, 26671124, 33927379, 30564623). Of those individuals, two were homozygous (1.0 pt), one was compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.1852G>A p.Gly618Arg, 1.0 pt), and one carried a variant classified as at least likely pathogenic in unknown phase (c.5529G>A p.Trp1843Ter, 0.25 pts) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702). The variant has also been reported to segregate with LGMD in two affected family members from one family (PMID: 26671124; PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/08/2025): PVS1_RNA, PP4_Strong, PM3_Strong, PP1, PM2_Supporting. -

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

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

May 26, 2017

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

This sequence change affects an acceptor splice site in intron 26 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with DYSF-related conditions (PMID: 26671124, 32400077). ClinVar contains an entry for this variant (Variation ID: 288644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Benign	0.92
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -32
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886043964; hg19: chr2-71796948;