Submissions for variant NM_000492.4(CFTR):c.1052C>G (p.Thr351Ser)

dbSNP: rs1800086

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046212	SCV000074225	uncertain significance	Cystic fibrosis	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 351 of the CFTR protein (p.Thr351Ser). This variant is present in population databases (rs1800086, gnomAD 0.07%). This missense change has been observed in individual(s) with pancreatitis, congenital absence of the vas deferens (CAVD), and mild or atypical cysitic fibrosis (PMID: 2395135, 9272157, 15858154, 16128988, 23670503). ClinVar contains an entry for this variant (Variation ID: 53174). 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 create or strengthen a 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265581	SCV000696818	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1052C>G (p.Thr351Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251742 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00019 vs 0.013), allowing no conclusion about variant significance. c.1052C>G has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, chronic pancreatitis and diffuse bronchiectasis, without strong evidence of causality (Mercier_1993, Dork_1997, Schrijver_2005, Bienvenu_2010, de Cid_2010, Dal Maso_2013, Masson_2013, Trujillano_2013, Grangeia_2018, Rispoli_2020, da Silva Filho_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. At-least two co-occurrences in cis with other pathogenic variants have been reported (e.g. CFTR c.3484C>T, p.Arg1162X; CFTR c.1521_1523del, p.Phe508del) (Mercier_1993, Dal Maso_2013), providing supporting evidence for a benign role. One of these reports was in an obligate carrier father of an individual with CF (in cis with p.Arg1162X, Mercier_1993) while the other was in an individual reportedly affected with CF who harbored a non-informative genotype attributed to a synonymous variant (p.Pro1290=) in trans (in cis with p.Phe508del, Del Maso_2013). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20167849, 33572515, 23670503, 20059485, 9272157, 18716917, 29589582, 16128988, 23951356, 8477260, 25735457, 32185651, 15858154, 23687349, 32819855, 19812525). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (n=9) and as benign (n=2) and Likely pathogenic without supporting evidence (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Eurofins Ntd Llc (ga)	RCV000588868	SCV000705166	uncertain significance	not provided	2018-02-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000006	SCV000885170	uncertain significance	Hereditary pancreatitis	2020-08-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000046212	SCV000886356	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588868	SCV001134106	uncertain significance	not provided	2021-02-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046212	SCV001178176	likely benign	Cystic fibrosis	2022-12-07	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	RCV001158654	SCV001320306	benign	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). 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome-Nilou Lab	RCV000046212	SCV001822034	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul	RCV000046212	SCV001977026	uncertain significance	Cystic fibrosis	2021-10-11	criteria provided, single submitter	research	This imprecision led to the belief that this variant is pathogenic. Despite this variant has been classified and reclassified over the course of time as pathogenic and lately as likely pathogenic (by Mendelics and Invitae), new functional evidence has shown that this variant does not alter CFTR function even when located in the same allele (in cis) as NM_000492.4(CFTR):2552G>T; p.Arg851Leu) and in trans with the most common pathogenic variant p.Phe508del (NM_000492.4(CFTR):1521_1523delCTT). Although in a pathogenic range due to its very low frequency in public databases (1000 Genomes, GnomAd Exons, GnomAd Genomes, etc., in people from different ethnicities), the aminoacid change promoted by this missense variant is practically synonymous for both amino acids residues are polar uncharged (at physiological pH), conserving the hydroxyl group in the side chain of this amino acid, basically having absent to little impact in the CFTR protein. Also, there is another missense variant in the same nucleotide position which has been classified as having uncertain significance (NM_000492.4(CFTR):c.1052C>T; p.Thr351Ile). Besides, prediction tools do not fully agree when predicting the deleteriousness of this variant. Therefore, the controversial data existing to date regarding this variant leads to the classification of uncertain significance. Brief Medical History: the patient was diagnosed with NBS and treated with pancreatic enzymes until the age of 2-3 y.o. The mother decided to stop giving any medication. Since then, the patient presented normal thrive and growth, normal stature, and was eutrophic throughout her life, which would not be expected given the patient's genotype. The patient is now 22 y.o. and has no history of chronic lung infections nor exacerbations or any other features compatible with Cystic Fibrosis. Sweat chloride tests have always been within borderline range (30-59 mM). Also, the patient is pancreatic-sufficient. In January 2020, the patient provided stool samples. Fecal elastase-1 levels in feces samples are within the normal range of the assay, which is a biomarker of pancreatic exocrine sufficiency. Other biochemical and hematological measurements to verify liver function were also normal throughout the patient's life.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046212	SCV002507379	uncertain significance	Cystic fibrosis	2020-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000588868	SCV002540891	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	PP3, PM2
PreventionGenetics, part of Exact Sciences	RCV001158654	SCV004117729	uncertain significance	CFTR-related disorder	2023-03-15	criteria provided, single submitter	clinical testing	The CFTR c.1052C>G variant is predicted to result in the amino acid substitution p.Thr351Ser. This variant has been reported in the heterozygous state in an individual with idiopathic chronic pancreatitis, an individual with CBAVD, and in an individual with clinical manifestations consistent with the spectrum of CF (Masson. 2013. Table S1 PubMed ID: 23951356; Larriba et al. 2005 PubMed ID: 16128988; Schrijver et al. 2005. Table 1 PubMed ID: 15858154). This variant has also been reported in the compound heterozygous state with a p.Phe508del variant in an individual with CBAVD (Doerk et al. 1997. Table 3 PubMed ID: 9272157) and in the homozygous state (and in cis with another CFTR variant) in an individual with a CFTR-related disorder (Trujillano. 2013. Table S3 PubMed ID: 23687349). In one individual with CF, this variant was one of three identified, and was in cis with a p.Phe508del variant (Dal'Maso et al. 2013 Table 3 PubMed ID: 23670503). To our knowledge, no functional or family studies are available to confirm the pathogenicity of the c.1052C>G change. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117180336-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000588868	SCV004158949	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001158654	SCV002507465	likely pathogenic	CFTR-related disorder	2020-05-28	no assertion criteria provided	clinical testing