ClinVar Miner

Submissions for variant NM_001039.4(SCNN1G):c.1532T>A (p.Leu511Gln)

gnomAD frequency: 0.00024  dbSNP: rs113234492
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV001543672 SCV001762359 uncertain significance Bronchiectasis with or without elevated sweat chloride 3 2021-07-16 criteria provided, single submitter clinical testing This SCNN1G variant (rs113234492) is rare (<0.1%) in a large population dataset (gnomAD: 45/282800 total alleles, 0.016%, no homozygotes) and has not been reported in the literature to our knowledge. Three bioinformatic tools queried predict that this substitution would be damaging, and the leucine residue at this position is strongly conserved across the vertebrate species assessed. This variant is not predicted to affect normal exon 12 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence we consider the clinical significance of c.1532T>A to be uncertain at this time.
Fulgent Genetics, Fulgent Genetics RCV005005255 SCV002775106 uncertain significance Bronchiectasis with or without elevated sweat chloride 3; Liddle syndrome 2; Pseudohypoaldosteronism, type IB3, autosomal recessive 2024-05-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003542345 SCV004249158 uncertain significance not provided 2024-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 511 of the SCNN1G protein (p.Leu511Gln). This variant is present in population databases (rs113234492, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SCNN1G-related conditions. ClinVar contains an entry for this variant (Variation ID: 1185021). 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 SCNN1G protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SCNN1G function (PMID: 23136006). 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.
GeneDx RCV003542345 SCV005325217 uncertain significance not provided 2023-08-08 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect via an increase in sodium ion flow, indicating a gain of function (Chen et al., 2013); 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: 24419567, 36305246, 23136006)

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