ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2856G>C (p.Met952Ile) (rs151048781)

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Total submissions: 13
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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 2021-03-03 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 in the literature. 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 (pathogenic/likely pathogenic, n=5; uncertain significance, n=3). 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2018-07-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001016788 SCV001177785 uncertain significance Inborn genetic diseases 2019-02-19 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. This variant was 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); however, the phase of these alterations was not confirmed (Steiner B et al. Hum. Mutat. 2011 Aug;32(8):912-20). In another study, this alteration was detected in an individual with CBAVD in conjunction with the p.R117H mutation (Ratbi I et al. Hum. Reprod. 2007;22(5):1285-91). This amino acid position is highly conserved in available vertebrate species. 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.
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].
Invitae RCV000577274 SCV001585351 pathogenic Cystic fibrosis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 952 of the CFTR protein (p.Met952Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs151048781, ExAC 0.01%). This missense change has been observed in combination with another CFTR variant in multiple individuals affected with congenital bilateral absence of the vas deferens or cystic fibrosis (PMID: 15287992, 15070876, 16272798, 10200050, 21520337, 23276700, 16980811). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 596906). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Nilou-Genome Lab RCV000577274 SCV001716366 likely pathogenic Cystic fibrosis 2021-05-18 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

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