ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This SCNN1G variant has been reported in multiple patients with Liddle syndrome. A functional study demonstrates that this variant increases ENaC activity and, thus, also increases the channel open probability, which is consistent with an abnormally high sodium reabsorption in the distal nephron. This variant (rs148985177) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the non-Finnish European subpopulation (gnomAD: 169/129046 alleles; 0.13%, no homozygotes). A single submitter in ClinVar classifies this variant as likely benign. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated and the asparagine residue at this position is highly evolutionarily conserved across all species assessed. Due to insufficient evidence, we consider the clinical significance of c.1589A>G to be uncertain at this time.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Observed in a young adult proband and parent with early onset hypertension and suspected Liddle syndrome, but was also present in a healthy blood donor and a control subject with low-normal blood pressure (Hiltunen et al., 2002); Published functional studies demonstrate a damaging gain-of-function effect, with N530S resulting in increased activity of epithelial sodium channels (Hiltunen et al., 2002; Boiko et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35685915, 29534496, 29229744, 26537344, 31655555, 35661050, 30028216, 12473862)

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. Experimental studies have shown that this missense change affects SCNN1G function (PMID: 12473862, 26537344). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCNN1G protein function. ClinVar contains an entry for this variant (Variation ID: 318359). This missense change has been observed in individual(s) with Liddle syndrome (PMID: 12473862). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs148985177, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 530 of the SCNN1G protein (p.Asn530Ser).

Variant summary: SCNN1G c.1589A>G (p.Asn530Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251320 control chromosomes. This frequency does not allow any conclusion about variant significance. c.1589A>G has been reported in the literature in the heterozygous state in at least one family affected with Liddle syndrome where it segregated with disease (e.g. Hiltunen_2002). Experimental in vitro studies in CHO cells and xenopus oocytes showed that this variant increases ENaC activity compared to wildtype (e.g. Boiko_2015, Hiltunen_2002). The following publications have been ascertained in the context of this evaluation (PMID: 26537344, 12473862). ClinVar contains an entry for this variant (Variation ID: 318359). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.