Submissions for variant NM_000492.4(CFTR):c.2506G>T (p.Asp836Tyr)

gnomAD frequency: 0.00040  dbSNP: rs201386642

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046610	SCV000074623	benign	Cystic fibrosis	2025-01-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224075	SCV000343987	uncertain significance	not provided	2017-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825894	SCV000696904	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2506G>T (p.Asp836Tyr) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 277324 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00044 vs 0.013), allowing no conclusion about variant significance. The variant, c.2506G>T, has been reported in the literature in compound heterozygosity with deltaF508 in patients with an equivocal diagnosis of CF as evidenced by negative sweat chloride levels and pancreatic sufficiency (example, Narzi_2007, deGracia_2005) as well as in patients with pancreatically insufficient classic CF phenotype who had two other pathogenic CFTR variants that could explain the diagnosis (Salinas_2016). These data provide supportive evidence for a benign role. Furthermore, in a recent study evaluating CFTR function by short circuit current measurement in a cell system, the variant of interest was found to have 121% of WT-CFTR function (Raraigh _2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, at-least one of whom has set a final classification as benign while another laboratory has re-classified the variant from likely pathogenic to uncertain significance citing overlapping evidence utilized in the context of this evaluation (Benign, n=1; VUS, n=5). Furthermore, the CFTR2 database reports this variant as not causative of CF. Based on the absence of concrete evidence supporting a disease causing outcome in literature spanning over 15 years as evidence outlined above, the variant is re-classified as benign.
Counsyl	RCV000046610	SCV000800606	uncertain significance	Cystic fibrosis	2017-10-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224075	SCV000885180	uncertain significance	not provided	2020-01-16	criteria provided, single submitter	clinical testing	The CFTR c.2506G>T; p.Asp836Tyr variant (rs201386642) has been reported in patients with diagnoses or symptoms of CF (des Georges 2004, de Gracia 2005, Schrijver 2005, CFTR2 database). However, p.Asp836Tyr has also been reported in two individuals with pancreatic-insufficient CF (Salinas 2016) who were compound heterozygotes for two known severe pathogenic variants (F508del and 2215insG). The p.Asp836Tyr variant is listed in ClinVar (Variation ID: 53505) and is found in the Latino population with an overall frequency of 0.18% (62/35414 alleles) in the Genome Aggregation Database. The aspartate at codon 836 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. However, the p.Asp836Tyr variant exhibits wildtype chloride channel activity in conductance assays (Raraigh 2018). Due to conflicting information, the clinical significance of the p.Asp836Tyr variant is uncertain at this time. References: CFTR2 database: https://www.cftr2.org/ de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Salinas D 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 May;7(2):289-99.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825894	SCV000967379	uncertain significance	not specified	2018-03-06	criteria provided, single submitter	clinical testing	The p.Asp836Tyr variant in CFTR has been reported in 2 individuals with cystic f ibrosis; however it was unclear if a second CFTR variant was found in these indi viduals (des Georges 2004, Schrijver 2005). It was also identified in the compou nd heterozygous state in 4 individuals who had at least one additional pathogeni c variant in CFTR (de Gracia 2005, Narzi 2007, Salinas 2016). In two of these in dividuals, two other pathogenic variants in CFTR were also identified, suggestin g that the p.Asp836Tyr variant may not be the primary cause of disease (Salinas 2016). This variant has also been reported by other clinical laboratories in Cli nVar (Variation ID# 53505) and has been identified in 0.17% (60/34400) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs201386642). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, due to conflicting evi dence, the clinical significance of the p.Asp836Tyr variant is uncertain. ACMG/A MP Criteria applied: PM3_Strong, BP2.
Ambry Genetics	RCV000046610	SCV001176659	uncertain significance	Cystic fibrosis	2024-05-30	criteria provided, single submitter	clinical testing	The p.D836Y variant (also known as c.2506G>T), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2506. The aspartic acid at codon 836 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was reported in trans with the p.F508del mutation in a newborn with a negative newborn screen and sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). In addition, this alteration was identified in an individual who had p.F508del and normal sweat test (de Gracia J et al. Thorax, 2005 Jul;60:558-63), as well as two affected newborns that had two known pathogenic mutations in CFTR (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624); however, the phase is not known. This alteration was also described in study cohorts of cystic fibrosis; however, clinical details were limited (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72; Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In CFBE cells, this variant demonstrated 122% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Genome-Nilou Lab	RCV000046610	SCV001822110	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224075	SCV002540900	uncertain significance	not provided	2021-09-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046610	SCV002573910	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3_STR, PP3, BS3, BP2
MGZ Medical Genetics Center	RCV002288550	SCV002580388	uncertain significance	Hereditary pancreatitis	2021-10-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224075	SCV003831633	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000046610	SCV004807191	uncertain significance	Cystic fibrosis	2024-03-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224075	SCV005625707	uncertain significance	not provided	2024-12-04	criteria provided, single submitter	clinical testing	The CFTR c.2506G>T (p.Asp836Tyr) variant (also known as D836Y) has been reported in the published literature in individuals affected with clinical manifestations associated with cystic fibrosis (PMID: 15698946 (2004), 15858154 (2005), 15994263 (2005), 34860163 (2021), 36409994 (2022)). It was also reported to occur in an asymptomatic individual with a CF-causing variant in trans (CFTR-France, (https://cftr.chu-montpellier.fr/)). Functional studies reported this variant to have chloride conductance activity from 47% (PMID: 38388235 (2024)) to 122% (PMID: 29805046 (2018)). This function was improved with pharmacological modulators to 91% in one study (PMID: 38388235 (2024)), however, an earlier study stated the variant may not respond as expected (PMID: 35527187 (2022)). The frequency of this variant in the general population, 0.0018 (62/35414 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224075	SCV000281608	likely pathogenic	not provided	2014-11-13	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734606	SCV005361296	uncertain significance	CFTR-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The CFTR c.2506G>T variant is predicted to result in the amino acid substitution p.Asp836Tyr. This variant has been reported on the opposite allele (in trans) with p.Phe508del in at least 2 individuals with a negative sweat test (de Gracia et al. 2005. PubMed ID: 15994263; Narzi et al. 2007. PubMed ID: 17594398). This variant has also been reported in an affected individual that carried two additional CFTR pathogenic variants (Salinas et al. 2016. PubMed ID: 27214204) and in a cohort of patients with cystic fibrosis, but no additional studies were performed to help assess its pathogenicity (des Georges et al 2004. PubMed ID: 15698946). In vitro studies in human cell lines suggest that this variant does not impact CFTR protein function (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.18% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar of benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/53505/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.