Submissions for variant NM_000492.4(CFTR):c.1219G>A (p.Glu407Lys)

gnomAD frequency: 0.00001  dbSNP: rs766063304

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193708	SCV001362744	uncertain significance	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1219G>A (p.Glu407Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 247126 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (4.5e-05 vs 0.013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1219G>A in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001243035	SCV001416165	uncertain significance	Cystic fibrosis	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 407 of the CFTR protein (p.Glu407Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital absence of vas deferens (PMID: 32777524). ClinVar contains an entry for this variant (Variation ID: 928981). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001243035	SCV002027393	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001243035	SCV002660799	uncertain significance	Cystic fibrosis	2022-08-25	criteria provided, single submitter	clinical testing	The p.E407K variant (also known as c.1219G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide position 1219. The glutamic acid at codon 407 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002491589	SCV002803878	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-04-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833747	SCV002080564	uncertain significance	CFTR-related disorders	2018-02-16	no assertion criteria provided	clinical testing