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

dbSNP: rs79074685

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173698	SCV000224842	uncertain significance	not provided	2016-01-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781283	SCV000919196	likely benign	not specified	2018-06-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1365G>T (p.Ala455Ala) alters a non-conserved nucleotide resulting in a synonymous change in exon 10 of the gene. 5/5 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 0.0071 in 238136 control chromosomes (in gnomAD). The observed variant frequency in the African (0.02640) and European Finnish (0.02228) subpopulations was roughly 2-fold of the expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013). Furthermore, the variant allele was indicated to be found with an even higher occurrence in the Japanese control population (in HGVD); i.e. with a frequency of 0.1348 (including 19 homozygotes), that would suggest this variant is likely a benign polymorphism. However, CFTR exon 10 and its flanking regions are known to have sequence identity with similar sequences in the human genome (that are located on several other chromosomes), therefore variants described in this exon could be variations observed in ectopic similar sequences. Previous reports also suggested that several variants described in exon 10 and its flanking regions may in fact be ectopic variations (PMID: 23261175, 25956447). As the technology utilized for genomic databases does not rule out pseudogene interference in this region, these data may not be reliable for assessing variant frequency. To our knowledge, no occurrence of c.1365G>T in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Another variant, c.1365G>A, that affects the same nucleotide and leads to the same codon effect (p.Ala455Ala) was classified as likely benign by our laboratory. Based on the evidence outlined above, the variant of interest was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001161866	SCV001323777	uncertain significance	CFTR-related disorder	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001480805	SCV001685128	likely benign	Cystic fibrosis	2022-10-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001480805	SCV001822049	likely benign	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001480805	SCV002696058	likely benign	Cystic fibrosis	2017-07-03	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000781283	SCV004847932	benign	not specified	2015-02-16	criteria provided, single submitter	clinical testing	p.Ala455Ala in exon 10 of CFTR: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 62/85992 of chromosomes across several diverse populations by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs79074685).