Submissions for variant NM_000492.4(CFTR):c.1365G>A (p.Ala455=)

gnomAD frequency: 0.00183  dbSNP: rs79074685

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245016	SCV000304469	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000245016	SCV000696838	benign	not specified	2022-10-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1365G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00047 in 229864 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00047 vs 0.013), allowing no conclusion about variant significance. c.1365G>A has been reported in one individual with chronic respiratory problems without evidence of causality (Shrijver_2005). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, though 4 classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV001085484	SCV001000713	benign	Cystic fibrosis	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001085484	SCV001171338	likely benign	Cystic fibrosis	2014-12-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001161865	SCV001323776	likely benign	CFTR-related disorder	2017-04-28	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.
Genome-Nilou Lab	RCV001588827	SCV001822050	likely benign	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256002	SCV002529673	benign	Hereditary pancreatitis	2020-11-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588680	SCV002774137	likely benign	not provided	2021-08-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588680	SCV003800550	likely benign	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001085484	SCV004024500	likely benign	Cystic fibrosis	2023-07-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000588680	SCV000700537	uncertain significance	not provided	2017-10-11	flagged submission	clinical testing
Natera, Inc.	RCV001161865	SCV002080581	likely benign	CFTR-related disorder	2019-08-05	no assertion criteria provided	clinical testing