ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.958T>G (p.Leu320Val) (rs144476686)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000029549 SCV000075309 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590210 SCV000697062 uncertain significance not provided 2016-09-29 criteria provided, single submitter clinical testing Variant summary: c.958T>G affects a non-conserved nucleotide, resulting in amino acid change from Leu to Val. 3/5 in-silico tools predict this variant to be benign. This variant was found in 50/121238 control chromosomes at a frequency of 0.0004124, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603). This mutation has been reported in association with various CF-related phenotypes or phenotypes in the CF spectrum (n=2; Lucarelli and Shrijver publications), CBAVD (n=1; sickkids), chronic pancreatitis (n=3; Pelletier, Keiles and Schwartz publications), and bronchiectasis (mentioned in Pelletier publication; exact number not known). The variant was also reported in newborns from newborn screening, and when not part of a complex allele and when in combination with a CF-C mutation, patients with this variant had normal sweat chloride levels and no cases of pancreatic insufficiency, which the authors suggest indicate the variant to be non-CF causing (Salinas_2016). Of note, this variant has been observed in three internal subjects undergoing testing for CF who also carry deltaF508 but phase and clinical information is not known. In HGMD, the variant has been listed to be associated with the CBAVD phenotype. In the sickkids db, this variant was reported to be observed in a CBAVD pt who was compound heterozygous for this variant and deltaF508. Taken all together, this variant was classified as VUS. More concordant occurrences and controls data are needed to establish a clear association to a specific phenotype.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590210 SCV000855679 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590210 SCV000889319 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing
Mendelics RCV000029549 SCV001137472 likely pathogenic Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000655 SCV001157681 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing The CFTR c.958T>G; p.Leu320Val variant (rs144476686) is historically considered to be mildly pathogenic due to its prevalence in individuals affected with congenital bilateral absence of vas deferens, pancreatitis, and other CFTR-related disorders (Sick Kids CFTR database, Dorfman 2010, Keiles 2006, Lucarelli 2010, Masson 2013, Pelletier 2010, Salinas 2016, Shrijver 2005, Schwartz 2009). However, this variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 35894), and is found in the general population with an overall allele frequency of 0.058% (163/282684 alleles, including 2 homozygotes) in the Genome Aggregation Database. The leucine at codon 320 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Sick Kids CFTR database link to L320V: Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 77(5):464-73. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Lucarelli M et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010 12(9):548-55. 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 8(8):e73522. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010 10(2-3):158-64. Salinas DB et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 7(2):289-99. Schwartz KM et al. Identification of cystic fibrosis variants by polymerase chain reaction/oligonucleotide ligation assay. J Mol Diagn. 2009 May;11(3):211-5.
Ambry Genetics RCV001019518 SCV001180888 uncertain significance Inborn genetic diseases 2020-01-02 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001165382 SCV001327571 uncertain significance 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. 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.

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