Submissions for variant NM_001130987.2(DYSF):c.4254dup (p.Ile1419fs)

dbSNP: rs398123786

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000537543	SCV000649683	pathogenic	Qualitative or quantitative defects of dysferlin	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile1401Hisfs*8) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Miyoshi muscular dystrophy, limb-girdle muscular dystrophy, and intermediate phenotypes (PMID: 16100712, 16891820, 17698709, 18853459, 19528035). ClinVar contains an entry for this variant (Variation ID: 94320). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000790760	SCV000701299	pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000984262	SCV001164466	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Ile1419HisfsTer8 variant (sometimes described as p.Ile1401HisfsTer8) in DYSFwas identified by our study in the compound heterozygous state, with a VUS, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.01335% (2/14978) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762804655). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and it has been reported pathogenic in ClinVar (Variation ID: 94320). The p.Ile1419HisfsTer8 variant in DYSF has been reported in 1 Moroccan, 1 Korean, and 6 unknown individuals with LGMD, including 3 individuals homozygous and 3 individuals heterozygous for the variant (PMID: 18853459, 16891820, 17698709). The presence of this variant in combination with a variant (reported pathogenic in ClinVar) and in an individual with LGMD increases the likelihood that the p.Ile1419HisfsTer8 variant is pathogenic (PMID: 18853459). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1419 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive LGMD, and this is a loss of function variant. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple reports of pathogenicity in ClinVar. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).
3billion	RCV002283453	SCV002573143	pathogenic	Distal myopathy with anterior tibial onset	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000094320 / PMID: 16891820 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002490697	SCV002811619	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2021-12-03	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000984262	SCV003922071	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B		criteria provided, single submitter	clinical testing	A Homozygote Frameshift variant c.4193_4194insC in Exon 39 of the DYSF gene that results in the amino acid substitution p.Ile1401fs*8 was identified. The observed variant has a minor allele frequency of 0.00006% in gnomAD exomes and novel in gnomAD genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 94320]. The observed variation has been reported previously in individual(s) with Miyoshi muscular dystrophy, limb-girdle muscular dystrophy, and intermediate phenotypes (Cho HJ, et.al., 2006). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003466984	SCV004194240	pathogenic	Miyoshi muscular dystrophy 1	2023-08-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000790760	SCV004243109	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000984262	SCV001132387	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-04-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984262	SCV001452768	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing