Submissions for variant NM_000492.4(CFTR):c.2856G>C (p.Met952Ile)

gnomAD frequency: 0.00006  dbSNP: rs151048781

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588974	SCV000696930	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2856G>C (p.Met952Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (8e-05 vs 0.013), allowing no conclusion about variant significance. c.2856G>C has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD; e.g. de Meeus_1997, Claustres_2004, Dayangac_2004, Uzun_2005, Ratbi_2007, Steiner_2011, Akinsal_2018). These data indicate that the variant is very likely to be associated with CBAVD disease. The variant has also been reported in multiple individuals affected with cystic fibrosis, however in at least one case, two additional pathogenic mutations in CFTR were found (phase not specified; e.g. Kammesheidt_2006), and in others, a second pathogenic mutation was not reported, and therefore evidence for causality in these cases could not be established (e.g. Desgeorges_1997, Onay_1998, Quint_2005, Soltysova_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant that creates the same amino acid change has been reported as pathogenic for CBAVD by our lab (c.2856G>A). The following publications have been ascertained in the context of this evaluation (PMID: 29484681, 17975025, 15287992, 15070876, 9254864, 20797923, 20021716, 20100616, 16980811, 25033378, 9521595, 10601093, 15948195, 17329263, 33374015, 26437683, 28544683, 21520337, 16272798, 16617247, 10200050). 15 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: 12 submitters classified the variant as likely pathogenic/pathogenic while 3 classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic in association with CBAVD.
Counsyl	RCV000577274	SCV000792125	uncertain significance	Cystic fibrosis	2017-06-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733156	SCV000861186	likely pathogenic	not provided	2018-05-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000733156	SCV000889301	likely pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The CFTR c.2856G>C (p.Met952Ile) variant has been reported in multiple individuals with congenital bilateral absence of the vas deferens (CBAVD) who were also positive for a pathogenic variant in the CFTR gene known to be associated with cystic fibrosis (CF) (PMID: 15070876 (2004), 16272798 (2005), 17329263 (2007), 21520337 (2011), 29484681 (2018)). This variant has been reported in individuals with a diagnosis of CF, but a second CFTR variant was either not identified or the genotype of the affected individual was not reported (PMID: 9254864 (1997), 11446424 (2001), 15948195 (2005), 16617247 (2006), 28544683 (2017)). It has also been reported in individuals with classic CF who were positive for two other variants that prevent the synthesis of CFTR protein (PMID: 16980811 (2006), 23276700 (2013)). The frequency of this variant in the general population (0.00011, 13/113696 chromosomes (Genome Aggregation Database (http://gnomad.broadinstitute.org))) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is deleterious. Based on the available information, this variant is classified as a likely pathogenic variant that is associated with CFTR-related disorders (CFTR-RD).
Illumina Laboratory Services, Illumina	RCV000577274	SCV000916183	likely pathogenic	Cystic fibrosis	2017-04-28	criteria provided, single submitter	clinical testing	The CFTR c.2856G>C (p.Met952Ile) missense variant has been reported in at least six studies and is found in a total of ten individuals with CFTR-related disorders. The p.Met952Ile variant was identified in a compound heterozygous state in five individuals with congenital bilateral absence of the vas deferens (CBAVD), four of whom were identified with the p.Phe508del variant in trans (Uzun et al. 2005; Steiner et al. 2011). The p.Met952Ile was also identified in a heterozygous state in three individuals with cystic fibrosis, one individual with oligospermia, and one individual with CBAVD (Desgeorges et al. 1997; Onay et al. 1998; Gallati et al. 2009; Steiner et al. 2011; Křenková et al. 2013). The p.Met952Ile variant was absent from 415 controls but is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Met952Ile variant is classified as likely pathogenic for CFTR-related disorders, and has most commonly been reported in patients with CBAVD. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002222	SCV001160096	likely pathogenic	not specified	2018-11-08	criteria provided, single submitter	clinical testing	The CFTR c.2856G>C; p.Met952Ile variant (rs151048781) is reported in the literature in multiple individuals with congenital absence of the vas deferens (CBAVD), including in individuals with a second pathogenic CFTR variant (Dayangac 2004, Ratbi 2007, Steiner 2011, Uzun 2007). While this variant has also been reported in several individuals with cystic fibrosis (CF), one individual already carried two other pathogenic variants (Desgeorges 2004, Krenkova 2013). The p.Met952Ile variant is reported in ClinVar (Variation ID: 53580) and is found in the general population with an overall allele frequency of 0.008% (20/251352 alleles) in the Genome Aggregation Database. The methionine at codon 952 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, another variant at this codon (p.Met952Thr) has been reported in individuals with CBAVD and is considered pathogenic (Casals 2000, Gilljam 1997, Wilschanski 2006). Though it is unclear if the p.Met952Ile variant causes classic CF, due to its strong association with CBAVD, this variant is considered to be likely pathogenic. References: 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; 15(7):1476-83. Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. Desgeorges M et al. Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet. 1997 Aug;100(2):279-83. Gilljam M et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med. 2004; 169(2):174-9. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. Uzun S et al. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005 Dec;207(4):279-85 Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006; 174(7):787-94.
CFTR-France	RCV001009476	SCV001169571	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000577274	SCV001177785	likely pathogenic	Cystic fibrosis	2023-08-14	criteria provided, single submitter	clinical testing	The p.M952I variant (also known as c.2856G>C), located in coding exon 17 of the CFTR gene, results from a G to C substitution at nucleotide position 2856. The methionine at codon 952 is replaced by isoleucine, an amino acid with highly similar properties. CFTR p.M952I (c.2586G>A or c.2586G>C) was originally identified in an individual with severe pulmonary disease, pancreatic insufficiency, and an elevated sweat chloride level; a second CFTR alteration was not identified (Desgeorges M et al. Hum. Genet., 1997 Aug;100:279-83). This variant was also detected in conjunction with pathogenic CFTR mutations in individuals with idiopathic chronic pancreatitis and congenital bilateral absence of the vas deferens (CBAVD) (Uzun S et al. Tohoku J. Exp. Med., 2005 Dec;207:279-85; Ratbi I et al. Hum. Reprod. 2007;22(5):1285-91; Steiner B et al. Hum. Mutat. 2011 Aug;32(8):912-20; Akinsal EC et al. Andrologia, 2018 Feb; Rudnik-Schöneborn S et al. Hum Reprod, 2021 02;36:551-559). 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, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577274	SCV001425446	uncertain significance	Cystic fibrosis	2020-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000577274	SCV001523282	uncertain significance	Cystic fibrosis	2020-01-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577274	SCV001585351	pathogenic	Cystic fibrosis	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 952 of the CFTR protein (p.Met952Ile). This variant is present in population databases (rs151048781, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens or cystic fibrosis (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53580). 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 with a positive predictive value of 80%. This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 10875853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000577274	SCV001716366	likely pathogenic	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000733156	SCV002022525	likely pathogenic	not provided	2021-11-16	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000733156	SCV002502710	likely pathogenic	not provided	2020-07-23	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000588974	SCV002581209	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-12-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000588974	SCV003841214	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000733156	SCV004010715	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PS1, PM2, PM5
Baylor Genetics	RCV003474555	SCV004213414	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-08-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000577274	SCV004807722	likely pathogenic	Cystic fibrosis	2024-03-29	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577274	SCV000679415	not provided	Cystic fibrosis		no assertion provided	literature only