Submissions for variant NM_001130987.2(DYSF):c.5132C>T (p.Ser1711Phe)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005154426	SCV005781633	likely pathogenic	Qualitative or quantitative defects of dysferlin	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1672 of the DYSF protein (p.Ser1672Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dysferlinopathy and/or limb-girdle weakness (PMID: 32528171, 33927379). This variant is also known as S1711F. 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 with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005241113	SCV005885173	uncertain significance	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5015C>T (p.Ser1672Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5015C>T has been reported in the literature in individual(s) from a cohort of dysferlinopathy, without strong evidence for causality (Charnay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications has been ascertained in the context of this evaluation (PMID: 33927379). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.