ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000029549 SCV000075309 benign Cystic fibrosis 2020-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526859 SCV000697062 uncertain significance not specified 2021-05-19 criteria provided, single submitter clinical testing Variant summary: CFTR c.958T>G (p.Leu320Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 251284 control chromosomes, including 2 homozygotes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00063 vs 0.013), allowing no conclusion about variant significance. c.958T>G has been reported in the literature in studies of individuals undergoing CFTR gene sequencing for CFTR-spectrum disorders such as idiopathic chronic pancreatitis, atypical CF phenotypes, and infertility/CBAVD (examples: Lucarelli_2010, Dorfman_2010, Pelletier_2010, Schrijver_2005, Keiles_2006, Schwartz_2009, Audrezet_2008, Masson_2013, Behar_2017) and in one case of an individual with Bohring-Opitz syndrome who harbored a disruptive frameshift mutation in the causative ASXL1 gene along with this variant and the pathogenic CFTR variant, p.F508del (Dangiolo_2015). However, the variant has also been reported in multiple individuals who carried a second CF-causing variant in trans and had a positive newborn screen for IRT, but were followed for 2-6 years and had no reported clinical CF phenotype (e.g. Salinas_2016). This finding suggests a benign role for the variant in association with CF, however other CFTR-related disorders could not be ruled out (e.g. Salinas_2016). In addition, the CFTR2 database reports the variant as non-CF causing in association with CF, stating that most individuals with this variant (combined with another CF-causing variant) will be healthy,athough a small number of individuals may develop mild symptoms or be diagnosed with a CFTR-related disorder (CFTR-RD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; uncertain significance, n=5; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS- possibly benign.
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 2020-02-26 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 none provided 2019-10-15 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 are uncertain whether this variant is neutral or deleterious (REVEL: 0.545). 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 The p.L320V variant (also known as c.958T>G), located in coding exon 8 of the CFTR gene, results from a T to G substitution at nucleotide position 958. The leucine at codon 320 is replaced by valine, an amino acid with highly similar properties. In our laboratory, this variant has been confirmed in trans with p.F508del in an individual with pancreatitis. This alteration accounted for one cystic fibrosis (CF) allele in a cohort of Hispanic individuals with a clinical diagnosis of CF; specific clinical data and a pathogenic mutation in trans were not described (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). In another study, p.L320V was identified in a patient with idiopathic pancreatitis and was classified as causing a variable phenotype, including congenital absence of the vas deferens, chronic pancreatitis, or bronchiectasis (Pelletier AL et al. Pancreatology. 2010;10(2-3):158-164). In a retrospective study of newborns with positive newborn screening by immunoreactive trypsinogen, children carrying p.L320V in trans with a pathogenic mutation did meet criteria for classic CF at follow-up (2 to 6 years); however, CFTR​-related disorders were not ruled out (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624; personal communication with Dr. Salinas). Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.
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.
Nilou-Genome Lab RCV001588829 SCV001822028 uncertain significance Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000029549 SCV001453955 likely benign Cystic fibrosis 2020-06-06 no assertion criteria provided clinical testing

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