Submissions for variant NM_006158.4(NEFL):c.1610A>G (p.Gln537Arg) (rs377121179)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics,Fulgent Genetics	RCV000764772	SCV000895910	uncertain significance	Charcot-Marie-Tooth disease, demyelinating, type 1f; Charcot-Marie-Tooth disease type 2E; CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000235949	SCV000294181	uncertain significance	not provided	2019-01-18	criteria provided, single submitter	clinical testing	The Q537R variant has been reported previously in an individual with congenital hypotonia; however, this individual was found to have two truncating variants on opposite alleles of the IGHMBP2 gene (Gonzaga-Jauregui et al., 2015). The Q537R variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The Q537R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter 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.
Invitae	RCV000203777	SCV000260583	uncertain significance	Charcot-Marie-Tooth disease type 2E	2018-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with arginine at codon 537 of the NEFL protein (p.Gln537Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs377121179, ExAC 0.06%). This variant has been reported in the literature in an individual with symptoms consistent with a mitochondrial disorder; however, the pathogenic nature of this variant was not established in this study (PMID: 24215330). ClinVar contains an entry for this variant (Variation ID: 220209). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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