Submissions for variant NM_001130987.2(DYSF):c.5635G>A (p.Val1879Met)

dbSNP: rs886042880

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000265900	SCV000337110	uncertain significance	not provided	2015-10-29	criteria provided, single submitter	clinical testing
Invitae	RCV001859602	SCV002256296	likely pathogenic	Qualitative or quantitative defects of dysferlin	2021-12-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. ClinVar contains an entry for this variant (Variation ID: 284471). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 26436962). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1840 of the DYSF protein (p.Val1840Met).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401247	SCV004122135	uncertain significance	not specified	2023-10-25	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5518G>A (p.Val1840Met) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 235658 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5518G>A has been reported in the literature in at least one compound heterozygous individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Ghaoui_2015). 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 has been ascertained in the context of this evaluation (PMID: 26436962). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.