rs398123796

Positions:

• chr2-71674223-TGA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001130987.2(DYSF):​c.5815_5816del​(p.Ser1939GlnfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: DYSF NM_001130987.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 10.0

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71674223-TGA-T is Pathogenic according to our data. Variant chr2-71674223-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 94344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71674223-TGA-T is described in Lovd as [Pathogenic]. Variant chr2-71674223-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5815_5816del	p.Ser1939GlnfsTer14	frameshift_variant	52/56	ENST00000410020.8
DYSF	NM_003494.4	c.5698_5699del	p.Ser1900GlnfsTer14	frameshift_variant	51/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.5698_5699del	p.Ser1900GlnfsTer14	frameshift_variant	51/55	1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.5815_5816del	p.Ser1939GlnfsTer14	frameshift_variant	52/56	1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251484 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461888 Hom.: 0 AF XY: 0.000128 AC XY: 93 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2023	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 individuals with limb-girdle muscular dystrophy or Miyoshi muscular dystrophy. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	The c.5698_5699delAG pathogenic variant in the DYSF gene has been reported previously in multiple unrelated individuals with dysferlinopathy who had a second DYSF variant identified (Takahashi et al., 2003; Klinge et al., 2010; Ankala et al., 2014). Due to use of alternative nomenclature, this variant has also been reported as c.6071_6072delAG (Takahashi et al., 2003). The deletion causes a frameshift starting with codon Serine 1900, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ser1900GlnfsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5698_5699delAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -

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

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Kids Neuroscience Centre, Sydney Children's Hospitals Network	-	The c.5698_5699del variant creates a frameshift and premature termination codon (p.(Ser1900Glnfs*14)). These transcripts are predicted to be degraded by nonsense mediated decay (NMD). Any mis -spliced DYSF transcripts that escape NMD encode DYSF protein lacking 181 amino acids from the C-terminus, including 42 amino acids from the C2 calcium dependant membrane targeting domain and the entire transmembrane domain. -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Ser1900Glnfs*14) 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 (rs778260292, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with Miyoshi myopathy (PMID: 9731526, 18853459, 19528035, 19594366, 23530687). This variant is also known as 6071,2delAG. ClinVar contains an entry for this variant (Variation ID: 94344). 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)		0.040		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: rs398123796; hg19: chr2-71901353;