Submissions for variant NM_001038.6(SCNN1A):c.1771C>T (p.Arg591Ter)

gnomAD frequency: 0.00003  dbSNP: rs771949339

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779111	SCV000915605	uncertain significance	Pseudohypoaldosteronism, type IB1, autosomal recessive	2018-10-16	criteria provided, single submitter	clinical testing	The SCNN1A c.1771C>T (p.Arg591Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00059 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive pseudohypoaldosteronism type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001114825	SCV001272736	benign	Bronchiectasis with or without elevated sweat chloride 2	2017-08-14	criteria provided, single submitter	clinical testing	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004735799	SCV005348661	uncertain significance	SCNN1A-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The SCNN1A c.1771C>T variant is predicted to result in premature protein termination (p.Arg591*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. While loss of function variants have been reported as causative, the p.Arg591* variant occurs in the last exon of the gene and it is unclear the impact this variant has on protein function. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.