rs786200898

Positions:

• chr2-71516241-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PP4_Strong PM3_Strong PVS1 PP1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.855+1del variant in DYSF, which is also known as NM_001130987.2: c.951+1del, occurs within the canonical splice donor site of intron 8. It is predicted to cause skipping of biologically relevant exon 8/55, resulting in an in-frame deletion of 21 amino acids (PVS1_Moderate). RNAseq data has confirmed that this variant results in in aberrant splicing, suggesting use of an alternative acceptor site that deletes the first basepair of DYSF exon 9 and leads to a frameshift and premature truncation p.(Val286TrpfsTer2) (PMID:36983702). This variant has been detected in at least 12 individuals with limb girdle muscular dystrophy (PMID:20544924, 17828519, 18853459, 36983702). Of those individuals, at least two were compound heterozygous for the variant and a pathogenic variant (c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID:20544924; c.3126G>A p.(Trp1024Ter): 1.0 pt, PMID:18853459), and at least one was homozygous (0.25 pts, PMID:18853459) (PM3_Strong). 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:18853459, 36983702). The variant was also reported to co-segregate with the disease in two affected family members from two families (PMID:18853459) (PP1, capped with PP4_Strong). The filtering allele frequency of the variant is 0.0009441 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 8/15286), 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_Moderate, PM3_Strong, PP4_Strong, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253921/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: DYSF NM_001130987.2 splice_donor, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.355

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 17 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.951+1delG		splice_donor_variant, intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.855+1delG		splice_donor_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.951+1delG		splice_donor_variant, intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.855+1delG		splice_donor_variant, intron_variant		1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.00000796 AC: 2 AN: 251384 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000219 AC: 32 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.0000261

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000523

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: 0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	Jan 08, 2025	The NM_003494.4: c.855+1del variant in DYSF, which is also known as NM_001130987.2: c.951+1del, occurs within the canonical splice donor site of intron 8. It is predicted to cause skipping of biologically relevant exon 8/55, resulting in an in-frame deletion of 21 amino acids (PVS1_Moderate). RNAseq data has confirmed that this variant results in in aberrant splicing, suggesting use of an alternative acceptor site that deletes the first basepair of DYSF exon 9 and leads to a frameshift and premature truncation p.(Val286TrpfsTer2) (PMID: 36983702). This variant has been detected in at least 12 individuals with limb girdle muscular dystrophy (PMID: 20544924, 17828519, 18853459, 36983702). Of those individuals, at least two were compound heterozygous for the variant and a pathogenic variant (c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 20544924; c.3126G>A p.(Trp1024Ter): 1.0 pt, PMID: 18853459), and at least one was homozygous (0.25 pts, PMID: 18853459) (PM3_Strong). 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: 18853459, 36983702). The variant was also reported to co-segregate with the disease in two affected family members from two families (PMID: 18853459) (PP1, capped with PP4_Strong). The filtering allele frequency of the variant is 0.0009441 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 8/15286), 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_Moderate, PM3_Strong, PP4_Strong, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	Variant summary: DYSF c.855+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant mRNA was absent in patient cells (Wenzel_2006), suggesting it undergoes nonsense mediated decay. The variant allele was found at a frequency of 8e-06 in 251384 control chromosomes (gnomAD). c.855+1delG has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Krahn_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 18853459). ClinVar contains an entry for this variant (Variation ID: 6684). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 23, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 13, 2024

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2023

This sequence change affects a splice site in intron 8 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 present in population databases (rs786200898, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with dysferlin deficient muscular dystrophy (PMID: 16010686, 18306167, 19528035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6684). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: 0
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200898; hg19: chr2-71743371;