ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588974 SCV000696930 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The c.2856G>C (p.Met952Ile) in CFTR gene is a missense variant that involves a conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is present in the broad control population dataset of ExAC at a low frequency of 0.00009 (11/121318), which does not exceed the maximum frequency for a pathogenic variant in CFTR gene (1.3%), suggesting this variant is not a common polymorphism. The variant has been reported in multiple CBAVD pts in compound heterozygosity with F508del, R117H, 5T without other clinical manifestations or family history suggestive of CF. Additionally, this variant was reported in at least 2 CF pts. However, it has also been reported in a patient with pancreatic insufficient CF (sweat chloride of 95mEq/L) who had 2 other pathogenic alterations (p.G542X and p.Y914X) in the CFTR gene. Also no functional studies demonstrating an effect of this variant on CFTR activity in-vitro or in-vivo have been reported. Taken together, the variant was classified as Likely Pathogenic for CF-RD (CBAVD) phenotype.
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 Insufficient or conflicting evidence
Johns Hopkins Genomics,Johns Hopkins University RCV000577274 SCV001425446 uncertain significance Cystic fibrosis 2020-03-02 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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