Submissions for variant NM_001130987.2(DYSF):c.3498T>A (p.Tyr1166Ter)

gnomAD frequency: 0.00003  dbSNP: rs758944159

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000385716	SCV000335160	pathogenic	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000407800	SCV000431793	likely pathogenic	Qualitative or quantitative defects of dysferlin	2017-04-27	criteria provided, single submitter	clinical testing	The DYSF c.3444T>A (p.Tyr1148Ter) stop-gained variant has not been reported in the literature; however variants that are predicted to have the same functional consequence as the c.3444T>A (p.Tyr1148Ter) variant have been associated with DYSF-related disorders including limb-girdle muscular dystrophy (LGMD) and Miyoshi myopathy (MM). Three studies have been published in which the p.Tyr1148Ter variant is found in a total of five individuals including two in a homozygous state and three in a compound heterozygous state (Kawabe et al. 2004; Klinge et al. 2010; Dominov et al. 2014). Kawabe et al. (2004) identified two related individuals, one with LGMD and one with MM who were homozygous for a DYSF c.3817-8TG>AA (p. Tyr1148Ter) variant. Klinge et al. (2010) identified an individual with MM who was compound heterozygous for a DYSF c.3444_3445delinsAA (p.Tyr1148Ter) variant and a second missense variant. Dominov et al. (2014) observed a DYSF c.3444_3445delTGinsAA (p.Tyr1148Ter) variant in two siblings with MM who were compound heterozygous for the variant and a second insertion variant. The c.3817-8TG>AA (p. Tyr1148Ter) variant was absent from 120 ethnically matched controls (Kawabe et al. 2004). Control data are unavailable for the c.3444T>A (p.Tyr1148Ter) variant and the c.3444_3445delinsAA (p.Tyr1148Ter) variant. The c.3444T>A (p.Tyr1148Ter) variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the evidence, the c.3444T>A (p.Tyr1148Ter) variant is classified as likely pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000407800	SCV003922178	pathogenic	Qualitative or quantitative defects of dysferlin	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Tyr1166Ter variant in DYSF was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 6684), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 6684), however the phase of these variants are unknown at this time. The p.Tyr1166Ter variant in DYSF has not been previously reported in individuals with limb-girdle muscular dystrophy 2 but has been identified in 0.005% (2/41402) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758944159). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 283206) and has been interpreted as pathogenic by Eurofins NTD LLC and as likely pathogenic by Illumina Laboratory Services. This nonsense variant leads to a premature termination codon at position 1166, which is predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 2. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 2. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015).