ClinVar Genomic variation as it relates to human health

This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 316 of the NF2 protein (p.Leu316Trp). This variant is present in population databases (rs750633919, gnomAD 0.01%). This missense change has been observed in individual(s) with bilateral vestibular schwannomas or breast cancer (PMID: 16983642, 35264596). ClinVar contains an entry for this variant (Variation ID: 380975). 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 not expected to disrupt NF2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NF2 function (PMID: 16532029). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces leucine with tryptophan at codon 316 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant does not impact interaction with HEI10, a cell cycle regulator, in a yeast two-hybrid assay (PMID: 16532029). This variant has been reported in an individual affected with bilateral vestibular schwannomas (PMID: 16983642). This variant has been identified in 8/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect on interaction with HEI10 (PMID: 16532029); This variant is associated with the following publications: (PMID: 16324214, 11756419, 17134719, 22482125, 35264596, 16983642, 16532029, 35332608)

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.