ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2855T>C (p.Met952Thr) (rs142773283)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046702 SCV000074715 uncertain significance Cystic fibrosis 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 952 of the CFTR protein (p.Met952Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs142773283, ExAC 0.06%), including at least one homozygous and/or hemizygous individual. This variant has been reported in individuals affected with congenital bilateral absence of the vas deferens (PMID: 10875853, 25087612) and chronic pancreatitis (PMID: 17003641, 20977904, 29589582), as well as control individuals (PMID: 24451227). Another individual with aquagenic keratoderma who had elevated chlorine and sodium levels was compound heterozygous for this variant (p.Met952Thr) and a deletion of exons 16-20 (PMID: 27026144). The clinical significance of these observations is uncertain. ClinVar contains an entry for this variant (Variation ID: 53579). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15287992, 15070876, 16272798, 10200050, 21520337, 23276700, 16980811). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255220 SCV000696929 uncertain significance not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: CFTR c.2855T>C (p.Met952Thr) 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 0.00027 in 255324 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (0.00027 vs 0.013), allowing no conclusion about variant significance. c.2855T>C has been reported in the literature in compound heterozygosity with a second pathogenic CFTR variant in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. Mak_1999, Casals_2000, Gilljam_2004, Wilschanski_2006). These data indicate that the variant may be associated with disease. The variant has also been reported in individuals with chronic pancreatitis (e.g. Keiles_2006, Schneider_2011) and cystic fibrosis (e.g. Mongodin_2002) without strong evidence for causality. The variant was also detected along with a deletion in CFTR in an individuals affected with Aquagenic Palmoplantar Keratoderma (AKP, e.g. Raynal_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants that affect this same amino acid residue have been classified internally as pathogenic (e.g. c.2856G>A, p.Met952Ile and c.2856G>C, p.Met952Ile), suggesting that variants in this region may be disease-causing. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely pathogenic (n=2) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587345 SCV000702493 uncertain significance not provided 2016-10-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624171 SCV000742086 uncertain significance Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587345 SCV000883592 likely pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000046702 SCV000916182 likely pathogenic Cystic fibrosis 2018-12-11 criteria provided, single submitter clinical testing The CFTR c.2855T>C (p.Met952Thr) missense variant has been reported in at least six studies and is reported in at least six individuals with CFTR-related disorders. Three of the individuals were males presenting with congenital bilateral absence of the vas deferens (CBAVD) in whom the p.Met952Thr variant was identified in a compound heterozygous state with the p.Phe508del variant (Mak et al. 1999; Casals et al. 2000; Wilschanski et al. 2006). In addition one individual with aquagenic palmoplantar keratoderma also carried the variant in a compound heterozygous state (Cabrol et al. 2016). The remaining two individuals presented with pancreatitis. In both individuals, the p.Met952Thr variant was identified in a heterozygous state along with additional variants in other genes including an intronic heterozygous variant in the PRSS1 gene and a homozygous variant in the SPINK1 gene (Keiles et al. 2006; Schneider et al. 2011). The p.Met952Thr variant was present in one of 274 controls (Wilschanski et al. 2006; Schneider et al. 2011; Martinez et al. 2014) and is also reported at a frequency of 0.00058 in the European (non-Finnish) population of the Exome Aggregation Consortium, including one individual with the variant in a homozygous state. This variant has not been reported in individuals presenting with classic CF and is thought to be associated with a mild CF phenotype when present in trans with a second pathogenic variant (Schneider et al. 2011). Another variant at the same amino acid position (p. Met952Ile) has also been identified in probands with CFTR-related disorders (Uzun et al. 2005; Steiner et al. 2011). Based on the collective evidence, the p.Met952Thr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mayo Clinic Laboratories, Mayo Clinic RCV000587345 SCV001715963 uncertain significance not provided 2019-12-26 criteria provided, single submitter clinical testing

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