Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 456 of the CFTR protein (p.Val456Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 14998948, 17035430, 22395041, 22423042, 25489051; Invitae). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 12544470). ClinVar contains an entry for this variant (Variation ID: 35821). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035821, PMID:12357328). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29805046). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:7505767). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.916>=0.6, 3CNET: 0.905>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002079). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 31126253, 30348612, 31005549, 22395041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_STR, PM5, PP3, PP4 - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Dec 08, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Jan 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.1367T>C (p.Val456Ala) variant in CFTR has been reported in the xompound heterozygous state with the CFTR p.Arg709X variant in at least 19 South Asian individuals with cystic fibrosis and in the homozygous state in 2 South Asian individuals with cystic fibrosis (McCormick 2002 PMID: 12357328, Uppaluri 2012 PMID: 22395041, Indika 2019 PMID: 31126253). Both homozygous patients had mild to moderate phenotypes resulting in delayed diagnosis. It has also been identified in 0.25% (12/4804) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency in the context of a prevalent disease. This variant has also been reported in ClinVar (Variation ID 35821). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vivo functional studies in humans provide evidence that this variant impacts protein function (Masica 2015 PMID: 25489051, Raraigh 2018 PMID: 29805046). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS3_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jan 20, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Missense variant c.1367T>C in Exon 10 of the CFTR gene that results in the amino acid substitution p.Val456Ala was identified. The observed variant has a minor allele frequency of 0.00020/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 35821). This variant has been identified in patients affected with Cystic Fibrosis (Indika NLR et al., 2019). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.V456A in CFTR (NM_000492.3) has previously been reported in homozygous and compound heterozygous state (Ziedalski et al. 2006;Uppaluri et al. 2012). Experimental studies reveal that the variant affects CFTR protein function (Raraigh et al 2018). The variant has been classified as Pathogenic in the ClinVar database. The p.V456A variant has a gnomAD exomes frequency of 0.02045 %. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val456Ala in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 30, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 13, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2024 | The p.V456A variant (also known as c.1367T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide position 1367. The valine at codon 456 is replaced by alanine, an amino acid with similar properties. This variant was described in an individual with bronchiectasis and elevated sweat chloride in conjunction with p.F508del; however, the phase was not provided (Ziedalski TM et al. Chest, 2006 Oct;130:995-1002). This variant was also reported in two affected South Asian individuals; one homozygous individual had severe obstructive lung disease with Pseudomonas infection, pancreatic sufficiency, and an intermediate sweat chloride level while the second individual had this variant in conjunction with p.R709* and exhibited pancreatic sufficiency, mild lung disease, and intermediate sweat chloride levels (Uppaluri L et al. J. Cyst. Fibros., 2012 Jul;11:312-5). In addition, this variant was detected in one individual with congenital absence of the vas deferens (CBAVD), but a second CFTR alteration was not reported (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6). Functional analysis of this variant in CFBE cells demonstrated 4% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |