Submissions for variant NM_015909.4(NBAS):c.2411A>G (p.Glu804Gly)

gnomAD frequency: 0.00001  dbSNP: rs1677547983

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Division of Biology and Genetics, University of Brescia	RCV001095793	SCV001250671	likely pathogenic	Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome; Infantile liver failure syndrome 2		criteria provided, single submitter	clinical testing	The p.Glu804Gly has not been previously described in literatura and is not reported in any population variant database. The p.Glu804Gly has been found in a child with a complex phenotype and in compound herterozugosity with the known pathogenic frameshift variant p.Ser230Glnfs*4. We conducted in vitro functional studies by site-directed mutagenesis and we provided evidence that the p.(Glu804Gly) variant affects different biological functions essential to the maintenance of intracellular homeostasis, i.e., the Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and secretion of collagen, thereby, partly explaining the associated phenotype.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856296	SCV002279027	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 804 of the NBAS protein (p.Glu804Gly). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects NBAS function (PMID: 32768688). 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 NBAS protein function. ClinVar contains an entry for this variant (Variation ID: 873540). This missense change has been observed in individual(s) with SOPH syndrome (PMID: 32768688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782647	SCV005394543	uncertain significance	not specified	2024-09-12	criteria provided, single submitter	clinical testing	Variant summary: NBAS c.2411A>G (p.Glu804Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249918 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2411A>G has been reported in the literature in at least one individual affected with SOPH syndrome (e.g. Ritelli_2020). This report does not provide unequivocal conclusions about association of the variant with Liver Failure Acute Infantile, Type 2. One publication reports experimental evidence evaluating an impact on protein function, specifically, altered subcellular lozaization, however, does not allow convincing conclusions about the variant effect (e.g. Ritelli_2020). ClinVar contains an entry for this variant (Variation ID: 873540). Based on the evidence outlined above, the variant was classified as uncertain significance.