Submissions for variant NM_000492.4(CFTR):c.960A>T (p.Leu320Phe)

gnomAD frequency: 0.00001  dbSNP: rs56093012

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000757879	SCV000886397	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000757879	SCV001180922	uncertain significance	Cystic fibrosis	2021-12-06	criteria provided, single submitter	clinical testing	The p.L320F variant (also known as c.960A>T), located in coding exon 8 of the CFTR gene, results from an A to T substitution at nucleotide position 960. The leucine at codon 320 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been identified in carrier cohorts (Morea A et al. Mol. Hum. Reprod., 2005 Aug;11:607-14; Pagin A et al. PLoS ONE, 2016 Feb;11:e0149426). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001165383	SCV001327572	uncertain significance	CFTR-related disorders	2017-08-21	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000757879	SCV002027381	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV000757879	SCV003262476	uncertain significance	Cystic fibrosis	2021-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 320 of the CFTR protein (p.Leu320Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs56093012, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. 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 phenylalanine 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323377	SCV004028735	uncertain significance	not specified	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.960A>T (p.Leu320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 4e-06 in 251280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.960A>T in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. However, it has been observed in the literature in unaffected carriers. The following publications have been ascertained in the context of this evaluation (PMID: 16126774, 26900683). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000757879	SCV001456056	uncertain significance	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing