ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.695T>A (p.Val232Asp) (rs397508783)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000047235 SCV000924250 pathogenic Cystic fibrosis 2018-08-31 reviewed by expert panel research
Counsyl RCV000047235 SCV000485370 likely pathogenic Cystic fibrosis 2015-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000732693 SCV000860673 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing
Mendelics RCV000047235 SCV000886269 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780160 SCV000917208 pathogenic not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.695T>A (p.Val232Asp) results in a non-conservative amino acid change in the ABC transporter type 1, transmembrane domain in 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 2e-05 in 246160 control chromosomes. This frequency is not higher than expected for a pathogenic variant in CFTR causing non-classic Cystic Fibrosis (2e-05 vs 0.013), allowing no conclusion about variant significance. The c.695T>A variant has been reported in the literature in numerous individuals affected with Cystic Fibrosis and non-classic Cystic Fibrosis, including CBAVD. These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000732693 SCV001134150 pathogenic not provided 2019-08-13 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780160 SCV001158550 likely pathogenic not specified 2019-06-14 criteria provided, single submitter clinical testing The CFTR c.695T>A; p.Val232Asp variant (rs397508783) is reported in the literature in the compound heterozygous state with another pathogenic variant causing pancreatic insufficiency in individuals affected with cystic fibrosis (see link to CFTR2 database, Casals 1997, Hirtz 2004). However, this variant is often associated with pancreatic sufficiency, and is also reported in individuals with mild CFTR-related disorders (Bernardino 2000, Casals 2000, Castellani 2008, Dal'Maso 2004, Masson 2013, Ooi 2012). This variant is reported as pathogenic or likely pathogenic by several laboratories in ClinVar (Variation ID: 54041), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 232 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show disrupted channel maturation, but some residual channel function remains (Caldwell 2011, Hirtz 2004, Loo 2014). Based on available information, this variant is considered to be likely pathogenic, and results in varying clinical consequences. References: Link to CFTR2 database: Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. Caldwell RA et al. Increased folding and channel activity of a rare cystic fibrosis mutant with CFTR modulators. Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L346-52. Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. 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. Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. Dal'Maso VB et al. Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis. J Bras Pneumol. 2013 Mar-Apr;39(2):181-9. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. Loo TW and Clarke DM. The cystic fibrosis V232D mutation inhibits CFTR maturation by disrupting a hydrophobic pocket rather than formation of aberrant interhelical hydrogen bonds. Biochem Pharmacol. 2014 Mar 1;88(1):46-57. 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. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62.
Baylor Genetics RCV001004237 SCV001163113 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009386 SCV001169239 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
CeGaT Praxis fuer Humangenetik Tuebingen RCV000732693 SCV001250501 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000047235 SCV001371799 pathogenic Cystic fibrosis 2020-01-12 criteria provided, single submitter clinical testing Previously reported disease-causing CFTR variant. See for phenotype information.
Invitae RCV000047235 SCV001575508 likely pathogenic Cystic fibrosis 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 232 of the CFTR protein (p.Val232Asp). The valine residue is weakly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is present in population databases (rs397508783, ExAC 0.001%). This variant has been reported in individuals with pancreatic-sufficient cystic fibrosis and congenital absence of the vas deferens (PMID: 10794365, 10875853, 16980811, 17329263, 21909392, 27086061). ClinVar contains an entry for this variant (Variation ID: 54041). Experimental studies have shown that this missense change result in aberrant CFTR protein folding and reduced protein expression (PMID: 19181854, 21642448, 21996038, 23924900). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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