Submissions for variant NM_000492.4(CFTR):c.958T>G (p.Leu320Val)

gnomAD frequency: 0.00043  dbSNP: rs144476686

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029549	SCV000075309	benign	Cystic fibrosis	2024-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526859	SCV000697062	uncertain significance	not specified	2024-03-01	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, although 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. The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 15858154, 17003641, 20059485, 20706124, 20460946, 19324992, 23951356, 27214204, 28465863, 28546993, 30134826, 26364555, 31036917, 32773111, 34583889). ClinVar contains an entry for this variant (Variation ID: 35894). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Eurofins Ntd Llc (ga)	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	2022-12-23	criteria provided, single submitter	clinical testing	The variant has been found in males diagnosed with congenital bilateral absence of the vas deferens (CBAVD) who also carried a second CFTR variant. The frequency of this variant in the general population, 0.002 (71/35418 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals diagnosed with Cystic Fibrosis (CF) (PMID: 15858154 (2005), 30134826 (2018)) and with atypical CF (PMID: 28546993 (2017)). The variant has also been reported in individuals with pancreatitis (PMID: 17003641 (2006), 18687795 (2008), 20460946 (2010), 30134826 (2018)), rhinosinusitis (PMID: 30134826 (2018)), and in an individual with Bohring-Opitz Syndrome (PMID: 26364555 (2015)). In a newborn screening study, the variant was identified as a non-causative variant for CF, but it could not rule out other CF-related disorders (PMID: 27214204 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000029549	SCV001137472	uncertain significance	Cystic fibrosis	2022-05-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590210	SCV001157681	uncertain significance	not provided	2023-09-28	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: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=174 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. PMID: 20059485 Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641 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. PMID: 20706124 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. PMID: 23951356 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. PMID: 20460946 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. PMID: 27214204 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. PMID: 15858154 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. PMID: 19324992
Ambry Genetics	RCV000029549	SCV001180888	uncertain significance	Cystic fibrosis	2024-06-06	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. 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 not 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). This alteration was also identified in an individual with an elevated sweat chloride and chronic pancreatitis. This individual also carried L997F however phase was not described (Sofia VM et al. Mol Med, 2018 07;24:38). 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.
Illumina Laboratory Services, Illumina	RCV001165382	SCV001327571	uncertain significance	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. 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.
Genome-Nilou Lab	RCV001588829	SCV001822028	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001801915	SCV002529743	uncertain significance	Hereditary pancreatitis	2021-04-04	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000590210	SCV003831647	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473147	SCV004213479	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1	2023-06-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590210	SCV005409328	uncertain significance	not provided	2024-04-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000029549	SCV001453955	likely benign	Cystic fibrosis	2020-06-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001165382	SCV004758413	uncertain significance	CFTR-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The CFTR c.958T>G variant is predicted to result in the amino acid substitution p.Leu320Val. The literature cites conflicting interpretations for this variant. In a series of 13 patients with the p.Leu320Val variant, none presented with pancreatic insufficiency (Salinas et al. 2016. PubMed ID: 27214204). Another group recently reported an additional patient with the c.958T>G variant without pancreatic insufficiency (Supplementary Table 1 in Saferali et al 2022. PubMed ID: 34996830). However, this variant has also been reported in two compound heterozygous individuals with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 15858154; Lucarelli et al. 2010. PubMed ID: 20706124). This variant is reported in 0.66% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, and two homozygous individuals have been documented. Due to conflicting literature reports and the lack of conclusive family and functional studies, the clinical significance of the c.958T>G (p.Leu320Val) variant is currently uncertain.