Submissions for variant NM_003494.3(DYSF):c.3504dup (p.Lys1169Glnfs)

dbSNP: rs886042504

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV004999208	SCV005620339	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2025-01-08	reviewed by expert panel	curation	The NM_003494.4: c.3504dup p.(Lys1169GlnfsTer6) variant in DYSF, which is also known as NM_001130987.2: c.3558dup p.(Lys1187GlnfsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 32/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three individuals with LGMD (PMID: 20544924, 21522182; ClinVar SCV003761541.2), including confirmed in trans with a pathogenic variant (c.855+1del, 1.0 pt, PMID: 20544924) (PM3). 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: 21522182). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). 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, PM3, PP4_Strong, PM2_Supporting.
Eurofins Ntd Llc (ga)	RCV000348399	SCV000334561	pathogenic	not provided	2015-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381377	SCV001579746	pathogenic	Qualitative or quantitative defects of dysferlin	2023-05-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1169Glnfs*6) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dysferlinopathy (PMID: 20544924). This variant is also known as c.3505insC. ClinVar contains an entry for this variant (Variation ID: 282861). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003105845	SCV004194582	pathogenic	Miyoshi muscular dystrophy 1	2021-10-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833324	SCV002082283	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2021-03-19	no assertion criteria provided	clinical testing
Genetics Research Group, Universidad San Francisco de Quito	RCV003105845	SCV003761541	pathogenic	Miyoshi muscular dystrophy 1	2023-01-27	no assertion criteria provided	clinical testing	We describe the c.3504dup (p.Lys1169Glnfs*6) in a family with a progressive muscular weakness for more than 20 years consisting of 6 siblings, 2 affected males, 1 affected female, one affected-death female, and 2 unaffected females. This variant has never been reported before in a study. However, its report has been described by laboratory companies.