Submissions for variant NM_006158.5(NEFL):c.986T>C (p.Leu329Pro)

dbSNP: rs876661290

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000762503	SCV000280000	uncertain significance	not provided	2018-10-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NEFL gene. The L329P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. The L329P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535984	SCV000639669	likely pathogenic	Charcot-Marie-Tooth disease type 2E	2023-05-08	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 NEFL protein function. ClinVar contains an entry for this variant (Variation ID: 234913). This missense change has been observed in individuals with clinical features of autosomal dominant Charcot-Marie-Tooth disease (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 329 of the NEFL protein (p.Leu329Pro).
CeGaT Center for Human Genetics Tuebingen	RCV000762503	SCV000892828	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764773	SCV000895911	uncertain significance	Charcot-Marie-Tooth disease type 1F; Charcot-Marie-Tooth disease type 2E; Charcot-Marie-Tooth disease, dominant intermediate G	2018-10-31	criteria provided, single submitter	clinical testing