Submissions for variant NM_001130987.2(DYSF):c.1722_1723insGTT (p.Leu574_Leu575insVal)

dbSNP: rs1446214240

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000731608	SCV000710095	likely pathogenic	not provided	2018-09-20	criteria provided, single submitter	clinical testing	The c.1668_1669insGTT variant in the DYSF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1668_1669insGTT variant is not observed in large population cohorts (Lek et al., 2016). The c.1668_1669insGTT variant results in an in-frame insertion of a single Valine residue at codon 557, denoted p.Leu556_Leu557insVal. We interpret c.1668_1669insGTT as a likely pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000731608	SCV000859452	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822847	SCV000963666	pathogenic	Qualitative or quantitative defects of dysferlin	2024-05-13	criteria provided, single submitter	clinical testing	This variant, c.1668_1669insGTT, results in the insertion of 1 amino acid(s) of the DYSF protein (p.Leu556_Leu557insVal), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with clinical features of dysferlinopathy and/or limb-girdle muscular dystrophy (PMID: 36983702; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 503800). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000731608	SCV003831280	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Jain Foundation	RCV000822847	SCV004032196	likely pathogenic	Qualitative or quantitative defects of dysferlin	2023-03-13	criteria provided, single submitter	research	This variant is rare with an allele frequency of 0.0022%. This variant has been observed in an individual with clinical features of dysferlinopathy and disease range dysferlin protein expression (PMID: 36983702). In this individual as well as a case reported by Invitae in ClinVar, this variant has been reported to be in the heterozygous state in trans with a second pathogenic DYSF variant. The ACMG classification criteria applied are PM2 moderate, PM3 moderate, and PP4 moderate. Based on the above data, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526716	SCV005040271	uncertain significance	not specified	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.1668_1669insGTT (p.Leu556_Leu557insVal) results in an in-frame insertion that is predicted to insert one amino acids into the encoded protein. The variant allele was found at a frequency of 4.2e-06 in 240810 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1668_1669insGTT has been reported in the literature in individuals affected with Dysferlinopathy (Rufibach_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36983702). ClinVar contains an entry for this variant (Variation ID: 503800). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003945451	SCV004760850	uncertain significance	DYSF-related disorder	2024-01-05	no assertion criteria provided	clinical testing	The DYSF c.1668_1669insGTT variant is predicted to result in an in-frame amino acid insertion (p.Leu556_Leu557insVal). This variant has been reported in the compound heterozygous state in an individual with presumed dysferlinopathy (Rufibach et al. 2023. PubMed ID: 36983702). This variant is reported in 0.0024% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.