Submissions for variant NM_001038.6(SCNN1A):c.1477T>C (p.Trp493Arg)

gnomAD frequency: 0.01653  dbSNP: rs5742912

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173721	SCV000224869	benign	not specified	2015-06-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000173721	SCV000270834	likely benign	not specified	2016-02-24	criteria provided, single submitter	clinical testing	The p.Trp552Arg variant in SCNN1A is prevalent in the general population with fr equencies up to 2.5% (413/16512) of South Asian chromosomes and 2.1% (1433/66734 ) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs5742912). While common, this variant has been claim ed to increase the risk of ischemic cerebrovascular events and cystic fibrosis-l ike clinical features up to 2 fold, particularly in carriers of a pathogenic CFT R variant, though these data are conflicting (Hsieh 2005, Azad 2009, Handschick 2012). In vitro functional studies provide some evidence that the p.Trp552Arg va riant may impact protein function, however these types of assays may not accurat ely reflect biological function. In summary, this variant is not expected to cau se disease on its own but a modifying role cannot be excluded.
PreventionGenetics, part of Exact Sciences	RCV000173721	SCV000306088	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000264087	SCV000380735	likely benign	Autosomal recessive pseudohypoaldosteronism type 1	2017-04-27	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). 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.
Illumina Laboratory Services, Illumina	RCV000009851	SCV000380736	likely benign	Bronchiectasis with or without elevated sweat chloride 2	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001528586	SCV001837189	benign	not provided	2021-04-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26453628, 26668308, 26764160, 15734793, 21917531, 20194130, 19462466)
Invitae	RCV001528586	SCV003244105	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
OMIM	RCV000009851	SCV000030072	pathogenic	Bronchiectasis with or without elevated sweat chloride 2	2009-07-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528586	SCV001740547	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000173721	SCV001928506	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173721	SCV001957274	benign	not specified		no assertion criteria provided	clinical testing