Submissions for variant NM_006158.5(NEFL):c.793T>G (p.Tyr265Asp)

dbSNP: rs1554497573

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516482	SCV000614191	uncertain significance	not specified	2017-07-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809657	SCV000949822	likely pathogenic	Charcot-Marie-Tooth disease type 2E	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 265 of the NEFL protein (p.Tyr265Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 447763). 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 NEFL protein function with a positive predictive value of 80%. This variant disrupts the p.Tyr265 amino acid residue in NEFL. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV001584230	SCV001811259	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002420299	SCV002676424	uncertain significance	Inborn genetic diseases	2020-08-04	criteria provided, single submitter	clinical testing	The p.Y265D variant (also known as c.793T>G), located in coding exon 1 of the NEFL gene, results from a T to G substitution at nucleotide position 793. The tyrosine at codon 265 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002490884	SCV002789612	uncertain significance	Charcot-Marie-Tooth disease type 1F; Charcot-Marie-Tooth disease type 2E; Charcot-Marie-Tooth disease, dominant intermediate G	2022-03-08	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV001027486	SCV001190059	uncertain significance	Hereditary motor neuron disease		no assertion criteria provided	provider interpretation