Submissions for variant NM_001038.6(SCNN1A):c.1216C>A (p.Leu406Ile)

gnomAD frequency: 0.00029  dbSNP: rs149484264

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215836	SCV000272420	uncertain significance	not specified	2015-09-02	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Leu465Ile var iant in SCNN1A has not been previously reported in individuals with pulmonary di sease, but has been identified in 33/66732 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149484264). C omputational prediction tools and conservation analysis suggest that the p.Leu46 5Ile variant may not impact the protein, though this information is not predicti ve enough to rule out pathogenicity. In summary, while the clinical significance of the p.Leu465Ile variant is uncertain, these data suggest that it is more lik ely to be benign.
Illumina Laboratory Services, Illumina	RCV000280531	SCV000380741	benign	Bronchiectasis with or without elevated sweat chloride 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000337981	SCV000380742	uncertain significance	Autosomal recessive pseudohypoaldosteronism type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002518202	SCV003289935	benign	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518203	SCV003707315	uncertain significance	Inborn genetic diseases	2022-09-27	criteria provided, single submitter	clinical testing	The c.1216C>A (p.L406I) alteration is located in exon 7 (coding exon 6) of the SCNN1A gene. This alteration results from a C to A substitution at nucleotide position 1216, causing the leucine (L) at amino acid position 406 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.