ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1367T>C (rs193922500)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000029474 SCV000924258 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029474 SCV000052124 pathogenic Cystic fibrosis 2019-11-01 criteria provided, single submitter clinical testing Variant summary: CFTR c.1367T>C (p.Val456Ala) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains 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 0.0002 in 244518 control chromosomes (genomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0002 vs 0.013), allowing no conclusion about variant significance. c.1367T>C has been reported in the literature in multiple individuals (in compound heterozygous or homozygous states) affected with Cystic Fibrosis (Danziger_2004, McCormik_2002, Ziedalski_2006, Raraigh_2018, Indika_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing <10% of wild-type chloride conductance (Raraigh_2018). Six ClinVar submitters (evaluation after 2014) classified the variant as likely pathogenic (3x) and pathogenic (3x), including one expert panel (CFTR2) classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000029474 SCV000486198 likely pathogenic Cystic fibrosis 2016-04-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000731635 SCV000859479 likely pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000731635 SCV000889282 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763570 SCV000894409 likely pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000029474 SCV000916181 pathogenic Cystic fibrosis 2018-09-06 criteria provided, single submitter clinical testing The CFTR c.1367T>C (p.Val456Ala) missense variant has been reported in five studies in which it is found in a total of nine individuals with CFTR-related disorders, including in one in a homozygous state and in eight in a compound heterozygous state (McCormick et al. 2002; Strom et al. 2003; Danziger et al. 2004; Ziedalski et al. 2006; Uppaluri et al. 2012). Three of the compound heterozygotes carried the common p.Phe508del variant on the second allele and four carried the same stop-gained variant on the second allele. One of the compound heterozygotes who presented with only congenital bilateral absence of the vas deferens was compound heterozygous for the p.Val456Ala variant and a 5T allele (a variable repeat located in intron 8 of the CFTR gene considered to be a variably penetrant mutation and to decrease the efficiency of intron 8 splicing) (Danziger et al. 2004). Additionally, Strom et al. (2003) identified the p.Val456Ala variant in a homozygous state in an asymptomatic proband suggesting that this is a mild allele. Control data are unavailable for this variant, which is reported at a frequency of 0.00306 in the South Asian population of the 1000 Genomes Project. The reported cases suggest the variant is more likely to lead to a classic cystic fibrosis phenotype when inherited in compound heterozygous state with a severe allele. Based on the evidence from the literature, the p.Val456Ala variant is classified as pathogenic for CFTR-related disorders. 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 RCV001001125 SCV001158265 likely pathogenic not specified 2019-03-15 criteria provided, single submitter clinical testing The CFTR c.1367T>C; p.Val456Ala variant (rs193922500) is reported as a CF-causing variant in the CFTR2 database, and CF patients with this variant are likely to be pancreatic sufficient (see CFTR2 database link). This variant is reported in the literature in both the homozygous and compound heterozygous states in CF patients (McCormick 2002, Uppaluri 2012); however, one report of an asymptomatic patient who is homozygous for this variant, suggests that it may be a mild CF variant (Strom 2003). Functional analysis of the variant protein shows approximately 4% of wildtype protein activity (Raraigh 2018). This variant is reported as likely pathogenic in ClinVar (Variation ID: 35821). It is found in the South Asian general population with an allele frequency of 0.16% (48/30028 alleles) in the Genome Aggregation Database. The valine at codon 456 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES CFTR2 database: McCormick J et al. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet. 2002 Oct;10(10):583-90. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14. Uppaluri L et al. Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians. J Cyst Fibros. 2012 Jul;11(4):312-5.
Baylor Genetics RCV001004447 SCV001163492 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009542 SCV001169637 pathogenic Cystic fibrosis; CFTR-related disorders 2018-03-09 criteria provided, single submitter curation the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000731635 SCV001450060 likely pathogenic not provided 2019-05-10 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000029474 SCV001478426 pathogenic Cystic fibrosis 2021-01-20 criteria provided, single submitter clinical testing
Baylor Genetics RCV001331274 SCV001523279 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-06-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000029474 SCV001574402 likely pathogenic Cystic fibrosis 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 456 of the CFTR protein (p.Val456Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs193922500, ExAC 0.1%). This variant has been observed in homozygosity or in combination with other CFTR variants in individuals with cystic fibrosis or congenital absence of the vas deferens (PMID: 22395041, 14998948, 17035430, 22423042, 25489051, Invitae). However, it has also been observed in homozygosity in an apparently unaffected individual (PMID: 12544470). ClinVar contains an entry for this variant (Variation ID: 35821). This variant has been reported to affect CFTR protein function (PMID: 29805046, 30046002). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000731635 SCV001714234 likely pathogenic not provided 2019-08-13 criteria provided, single submitter clinical testing PS3, PM2, PP3, PP5

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