Submissions for variant NM_001130987.2(DYSF):c.4057G>A (p.Glu1353Lys)

gnomAD frequency: 0.00001  dbSNP: rs758993965

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV005253143	SCV005903540	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2025-02-25	reviewed by expert panel	curation	The NM_003494.4: c.4003G>A variant in DYSF, which is also known as NM_001130987.2: c.4057G>A (p.Glu1353Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1335, p.(Glu1335Lys). This variant has been reported in at least six patients with dysferlinopathy (PMID: 14678801, 17070050, 21522182, 22194990, 33613410, 36983702), including in a homozygous state in at least one individual without known familial consanguinity (0.5 pt; PMID 17070050, 22194990) and confirmed in trans with a likely pathogenic or pathogenic variant in two individuals (c.1639-6T>A p.(Gly547AlafsTer24), 1 pt, PMID: 36983702; c.2875C>T p.(Arg959Trp), 1 pt, PMID: 14678801) (PM3_Strong). At least one of the patients with a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 17070050, 21522182, 22194990, 33613410, 36983702) (PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 14678801; PP1). The highest minor allele frequency is 0.0001309 (2/15284 genome alleles) in the Admixed American population of gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Glu1335Lys protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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; 02/25/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812166	SCV000952470	pathogenic	Qualitative or quantitative defects of dysferlin	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1335 of the DYSF protein (p.Glu1335Lys). This variant is present in population databases (rs758993965, gnomAD 0.003%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and/or Miyoshi myopathy (PMID: 14678801, 21522182, 22194990). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 655896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001089590	SCV001477224	likely pathogenic	not provided	2020-03-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. 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.
Baylor Genetics	RCV003461204	SCV004194178	pathogenic	Miyoshi muscular dystrophy 1	2023-12-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000812166	SCV004847353	likely pathogenic	Qualitative or quantitative defects of dysferlin	2023-10-17	criteria provided, single submitter	clinical testing	The p.Glu1353Lys variant in DYSF (also reported as p.Glu1335Lys in the literature) has been reported in the compound heterozygote state with another disease causing variant in DYSF in at least 2 individuals and in the homozygous state in at least 1 individual with limb-girdle muscular dystrophy or Miyoshi myopathy and segregated with disease in 1 affected relative from 1 family. All of these individuals had confirmed absent or reduced expression of dysferlin protein (Cagliani 2003 PMID: 14678801, De Luna 2007 PMID: 17070050, Cacciottolo 2011 PMID: 21522182, Zhang 2020 PMID: 33613410). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 655896) and has been identified in 0.01% (2/15284) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive dysferlinopathies including limb-girdle muscular dystrophy and Miyoshi myopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP1, PP3, PP4.
Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology	RCV001089590	SCV001244911	pathogenic	not provided	2019-07-01	no assertion criteria provided	reference population
Natera, Inc.	RCV001830775	SCV002082305	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-12-11	no assertion criteria provided	clinical testing