Submissions for variant NM_000492.4(CFTR):c.1117G>A (p.Asp373Asn)

gnomAD frequency: 0.00003  dbSNP: rs556880586

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000149423	SCV000886165	uncertain significance	Cystic fibrosis	2023-10-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149423	SCV001506096	uncertain significance	Cystic fibrosis	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 373 of the CFTR protein (p.Asp373Asn). This variant is present in population databases (rs556880586, gnomAD 0.008%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 27022295). ClinVar contains an entry for this variant (Variation ID: 161998). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000149423	SCV001822037	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155087	SCV003844692	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1117G>A (p.Asp373Asn) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a canonical 3' acceptor site. One predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1117G>A has been reported in the literature in a patient with respiratory and gastric symptomatology and borderline sweat chloride tests with no second allele detected (Sanchez_2016) and in a patient frm a CF patient registry (da Silva Filho_2021). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 27022295, 32819855). ClinVar contains an entry for this variant (Variation ID: 161998). Based on the evidence outlined above, the variant was classified as uncertain significance.
Unidad de Estudios Geneticos y Forenses, Instituto Venezolano de Investigaciones Cientificas	RCV000149423	SCV000196070	pathogenic	Cystic fibrosis	2013-10-01	no assertion criteria provided	research
Natera, Inc.	RCV001826800	SCV002078194	uncertain significance	CFTR-related disorder	2018-10-04	no assertion criteria provided	clinical testing