Submissions for variant NM_000492.4(CFTR):c.3041A>G (p.Tyr1014Cys)

gnomAD frequency: 0.00019  dbSNP: rs149279509

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000987964	SCV001981587	uncertain significance	Cystic fibrosis	2017-10-03	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000586855	SCV000202440	uncertain significance	not provided	2018-07-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586855	SCV000601086	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0038 (39/10364 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been identified alone or with another pathogenic CF variant in individuals with known or suspected cystic fibrosis or with CFTR-related disorders (PMIDs: 11466205 (2001), 15151509 (2004), 17331079 (2007), 23951356 (2013), 25383785 (2015), 27449771 (2016), 28546993 (2017), 30888834 (2019), and 31665830 (2020)). Functional studies indicated that this variant shows a moderate decrease in CFTR protein function (PMIDs: 29805046 (2018), 30888834 (2019), and 34996830 (2022)). Taking into account the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152997	SCV000696943	uncertain significance	not specified	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3041A>G (p.Tyr1014Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 0.00028 in 251138 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00046 vs 0.013), allowing no conclusion about variant significance. c.3041A>G has been reported in the literature in individuals affected with Non-Classic Cystic Fibrosis and CFTR-related phenotypes, including CBAVD, pancreatitis, bronchiectasis, and CF (examples: Casals_2000, Casals_2004, Alonso_2007, Fuster_2007, Audrezet_2008, Werlin_2014, Sanchez_2016, Behar_2017, Zeiger_2019, Saferali_2022). In the majority of these cases, a second mutation was not specified, however at least four patients with a CF phenotype have been reported to carry the variant in compound heterozygosity with another known pathogenic variant (e.g. Fuster 2007, Behar 2017). In addition, the variant has been reported as compound heterozygous genotype in two patients with recurrent acute pancreatitis who carried another pathogenic CFTR variant (though the phase was not tested). These patients were assessed to have abnormal nasal potential differences and elevated sweat chloride levels, indicating a loss of CFTR function (e.g. Werlin 2014). Collectively, these data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. In these studies, cells expressing the variant with or without a second pathogenic mutation had approximately 74-75% wild-type CFTR function (e.g. Raraigh_2018, McCague_2019). Disease association was indeterminate based upon these findings. The CFTR2 database reports that there is not enough information to determine whether the p.Y1014C variant is disease-causing at this time. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 18687795, 31036917, 28546993, 25203624, 15151509, 10875853, 17663888, 29589582, 26182300, 11466205, 26847993, 25880441, 23951356, 30888834, 29805046, 34996830, 27022295, 25087612, 29669919, 23687349, 25383785, 27449771, 31665830, 19812525). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=12 and Likely Pathogenic, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the conflicting clinical and functional evidence outlined above and awaiting additional peer consensus, the variant was classified as uncertain significance.
Mendelics	RCV000987964	SCV001137490	uncertain significance	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000987964	SCV001179468	uncertain significance	Cystic fibrosis	2023-04-04	criteria provided, single submitter	clinical testing	The p.Y1014C variant (also known as c.3041A>G), located in coding exon 19 of the CFTR gene, results from an A to G substitution at nucleotide position 3041. The tyrosine at codon 1014 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first described in the heterozygous state in two males presenting with congenital bilateral absence of the vas deferens (CBAVD) (Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83; Larriba S et al. Biol. Reprod., 2001 Aug;65:394-400). This variant was also reported in two individuals with abnormal nasal potential differences and acute recurrent pancreatitis. One of these individuals had a sweat chloride level of 100 mEq/L and also carried p.W1282*, while the other individual had a sweat chloride level of 54 mEq/L and carried p.R117H; the phase was not determined in either individual (Werlin S et al. J. Pediatr. Gastroenterol. Nutr., 2015 May;60:675-9). In another study, this variant was found in an individual with bronchiectasis and a negative sweat chloride level in conjunction with the 5T allele; however, the phase was not determined (Casals T et al. Clin. Genet., 2004 Jun;65:490-5). This variant was also detected in three individuals with chronic pancreatitis, both with and without another CFTR alteration (de Cid R et al. Pancreas, 2010 Mar;39:209-15). In CFBE cells, chloride conductance for this variant was 74% of wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001163493	SCV001325540	uncertain significance	CFTR-related disorder	2017-04-28	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000987964	SCV001441554	uncertain significance	Cystic fibrosis	2020-10-23	criteria provided, single submitter	clinical testing	CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586855	SCV001474122	uncertain significance	not provided	2019-09-20	criteria provided, single submitter	clinical testing	The CFTR c.3041A>G; p.Tyr1014Cys variant (rs149279509) is reported in the literature in multiple individuals affected with cystic fibrosis (Alonso 2007, Behar 2017, Sanchez 2016) or CFTR-related disorders (Audrezet 2008, Casals 2000, Casals 2004, de Cid 2010, Larriba 2001, Masson 2013, Trujillano 2013), in some of whom a second pathogenic CFTR variant was identified. This variant is reported in ClinVar (Variation ID: 53638), and is found in the Ashkenazi Jewish population with an allele frequency of 0.38% (39/10364 alleles) in the Genome Aggregation Database. The tyrosine at codon 1014 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a moderate decrease in protein function (Raraigh 2018). However, based on available information, the clinical significance of the p.Tyr1014Cys variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. Audrezet MP et al. Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. J Mol Diagn. 2008 Sep;10(5):424-34. Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. Casals T et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490-5. de Cid R et al. Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas. 2010 Mar;39(2):209-15. Larriba S et al. Adenosine triphosphate-binding cassette superfamily transporter gene expression in severe male infertility. Biol Reprod. 2001 Aug;65(2):394-400. 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(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. 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. Sanchez K et al. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants. Appl Clin Genet. 2016 Mar 8;9:33-8.
GeneDx	RCV000586855	SCV001986041	uncertain significance	not provided	2023-01-12	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic variant in individuals with cystic fibrosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Behar 2017); Observed in individuals with pancreatitis and other CFTR-related disorders (Casals 2004, de Cid 2010, Werlin 2015); Published functional studies are inconclusive: does not significantly affect CFTR function (Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of unknown significance in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 26847993, 11466205, 27449771, 15151509, 19812525, 25383785, 25087612, 23951356, 10875853, 29589582, 27022295, 25203624, 17331079, 18687795, 23687349, 29805046, 32003480, 28546993, 34996830, 31036917, 32734384, 36207272, 31665830, 35652053, 34797250, 33922413, 34842611, 32773111, 35913788)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000987964	SCV002507378	uncertain significance	Cystic fibrosis	2020-10-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504942	SCV002812059	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-05	criteria provided, single submitter	clinical testing
Invitae	RCV000987964	SCV003029992	uncertain significance	Cystic fibrosis	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1014 of the CFTR protein (p.Tyr1014Cys). This variant is present in population databases (rs149279509, gnomAD 0.4%). This missense change has been observed in individual(s) with known or suspected with cystic fibrosis and idiopathic chronic pancreatitis, recurrent acute pancreatitis, pancreatic cancer, gastric cancer, and congenital bilateral absence of the vas deferens (PMID: 11466205, 17331079, 17663888, 18687795, 23951356, 25383785, 26182300, 28546993). ClinVar contains an entry for this variant (Variation ID: 53638). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV001163493	SCV004115988	uncertain significance	CFTR-related disorder	2024-01-03	criteria provided, single submitter	clinical testing	The CFTR c.3041A>G variant is predicted to result in the amino acid substitution p.Tyr1014Cys. This variant has been reported in multiple individuals with cystic fibrosis and CFTR-related phenotypes including congenital absence of the vas deferens, pancreatitis, and bronchiectasis (Casals et al. 2000. PubMed ID: 10875853; Larriba et al. 2001. PubMed ID: 11466205; Casals et al. 2004. PubMed ID: 15151509; de Cid et al. 2010. PubMed ID: 19812525; Werlin et al. 2015. PubMed ID: 25383785; Sánchez et al. 2016. PubMed ID: 27022295; Behar et al. 2017. PubMed ID: 28546993; Zeiger et al. 2020. PubMed ID: 31665830). In vitro functional studies indicate that the p.Tyr1014Cys variant retains approximately 74-75% of CFTR function compared to control (Raraigh et al 2018. PubMed ID: 29805046; McCague et al. 2019. PubMed ID: 30888834). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In the ClinVar database, multiple clinical laboratories interpret this variant as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/53638/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003474566	SCV004213541	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1	2023-03-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586855	SCV004224086	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	PP3
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586855	SCV001551619	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CFTR p.Tyr1014Cys variant was identified in the literature in cases of Cystic Fibrosis (CF) or congenital absence of the vas deferens (CAVD) as well as in healthy controls. The variant was identified in the heterozygous state in 3/176 Israeli CF patients lacking a known molecular diagnosis and in 2/977 Spanish families with CF (freq=0.001) (Behar_2017_PMID:28546993; Alonso_2007_PMID:17331079). The variant was also found in 1/134 men (freq=0.004) with CAVD (Casals_2000_PMID:10875853). A study of 512 unaffected Portuguese children reported the Y1014C variant in the heterozygous state in 2 children (Grangeia_2018_PMID:29589582). Functional studies of multiple known or suggested CF variants showed that the Y1014C variant retained ~74% of wildtype function, compared to less than 1% of wildtype function from the well-known deltaF508 CF mutation; this does not suggest a strong functional effect of the Y1014C variant (Raraigh_2018_PMID:29805046). The variant was also identified in dbSNP (ID: rs149279509), LOVD 3.0 and ClinVar (classified as a VUS by EGL Genetic Diagnostics, Quest Diagnostics and Integrated Genetics/Laboratory Corporation of America) but was not found in Cosmic. The variant was identified in control databases in 73 of 282520 chromosomes at a frequency of 0.000258 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10364 chromosomes (freq: 0.003763), Other in 4 of 7198 chromosomes (freq: 0.000556), Latino in 17 of 35350 chromosomes (freq: 0.000481) and European (non-Finnish) in 13 of 129000 chromosomes (freq: 0.000101); it was not observed in the African, East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Tyr1014 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001163493	SCV002507464	likely pathogenic	CFTR-related disorder	2020-10-22	no assertion criteria provided	clinical testing