ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1052C>G (p.Thr351Ser) (rs1800086)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588868 SCV000885170 pathogenic not provided 2018-01-17 criteria provided, single submitter clinical testing The CFTR c.1052C>G; p.Thr351Ser variant (rs1800086) has been reported in individuals with CFTR-related disorders (Masson 2013, Trujillano 2013), and considered a polymorphism by the SickKids CFTR database (see link). It is listed in ClinVar (variation ID: 53174), and observed in the general population at a frequency of 0.02% in the Genome Aggregation Database. The threonine at codon 351 is highly conserved, and computational algorithms (Alamut v.2.11) predict that the variant creates a cryptic splice donor within the exon. The variant has been observed in patients with pancreatitis, when found in-trans with p.Phe508del. Based on the above information, this variant is classified as pathogenic - mild. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=864 Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug;8(8):e73522. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588868 SCV000705166 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000046212 SCV000074225 uncertain significance Cystic fibrosis 2018-12-28 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.
Mendelics RCV000046212 SCV000886356 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing

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