ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1052C>G (p.Thr351Ser) (rs1800086)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046212 SCV000074225 uncertain significance Cystic fibrosis 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 351 of the CFTR protein (p.Thr351Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs1800086, ExAC 0.03%). This variant has been reported in individuals with pancreatitis, congenital absence of the vas deferens (CAVD), and mild or atypical cysitic fibrosis (PMID: 2395135, 9272157, 16128988, 23670503, 15858154). However, a pathogenic variant was observed on the opposite allele in only one of these individuals (PMID: 9272157), and in that report only a small number of common mutations were tested. As a result, it is uncertain if this c.1052C>G variant contributes to disease in any of these affected individuals. 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, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588868 SCV000696818 likely benign not provided 2016-12-16 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1052C>G (p.Thr351Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 23/121916 control chromosomes at a frequency of 0.0001887, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant is reported in multiple publications as a "polymorphism" and is reported as being found in cis with a pathogenic CFTR variant in two individuals (Dal Maso_2013, Mercier_1993), strong evidence for the benign nature of the variant. Therefore this variant was classified as likely benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2020-02-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017142 SCV001178176 uncertain significance Inborn genetic diseases 2020-09-29 criteria provided, single submitter clinical testing The p.T351S variant (also known as c.1052C>G), located in coding exon 8 of the CFTR gene, results from a C to G substitution at nucleotide position 1052. The threonine at codon 351 is replaced by serine, an amino acid with similar properties. This variant has been reported in trans with a disease-causing mutation in an unaffected father of a cystic fibrosis patient (Mercier B et al. Hum. Mutat., 1993;2:16-20) as well as in an individual with diffuse bronchiectasis and normal sweat chloride levels (Bienvenu T et al. Am. J. Respir. Crit. Care Med., 2010 May;181:1078-84). This alteration was reported to be homozygous (and in cis with a second variant on both alleles) in a patient with a CFTR-related disorder (Trujillano et al. J Med Genet. 2013;50(7):455-62). Another study described this variant to be in cis with p.F508del in a patient with features of cystic fibrosis; a second disease causing alteration was not reported (Dal'Maso et al. J Bras Pneumol. 2013;39(2):181-9). This amino acid position is highly 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.
Illumina Clinical Services Laboratory,Illumina RCV001158654 SCV001320306 benign CFTR-related disorders 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.
Nilou-Genome Lab RCV000046212 SCV001822034 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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