Submissions for variant NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

dbSNP: rs193922500

Total submissions: 27

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
Eurofins Ntd Llc (ga)	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	2022-12-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0016 (48/30028 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (CF) in a heterozygous state with another pathogenic variant (PMID: 12357328 (2002), 17035430 (2006), 22395041 (2012), 30348612 (2019)), and in a homozygous state (PMID: 22395041 (2012), 31126253 (2019)). It has also been reported in an asymptomatic individual in a homozygous state (PMID: 12544470 (2003)). Additionally, the variant was also reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 14998948 (2004)). A functional study reported this variant resulted in only 4% of protein function compared to the wild type (PMID: 29805046 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763570	SCV000894409	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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: https://cftr2.org/ 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 disorder	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 and Genomics, 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].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029474	SCV001574402	pathogenic	Cystic fibrosis	2024-01-28	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000731635	SCV001714234	likely pathogenic	not provided	2019-08-13	criteria provided, single submitter	clinical testing	PS3, PM2, PP3, PP5
GeneDx	RCV000731635	SCV001758624	pathogenic	not provided	2024-07-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (PMID: 29805046); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29805046, 29216686, 25489051, 28502372, 22395041, 31126253, 31005549, 14998948, 12544470, 24149827, 12357328, 31036917, 34842611, 32366966, 32734384, 22423042, 35652053, 35857025, Conti 2023[Review], 35761057, 34782259, 37313453, 17035430, 38515211)
Revvity Omics, Revvity	RCV000731635	SCV002022516	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000029474	SCV002059220	pathogenic	Cystic fibrosis	2020-04-30	criteria provided, single submitter	clinical testing
3billion	RCV000029474	SCV002318684	pathogenic	Cystic fibrosis	2022-03-22	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000029474	SCV002573848	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	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
Ambry Genetics	RCV000029474	SCV002701184	likely pathogenic	Cystic fibrosis	2024-01-23	criteria provided, single submitter	clinical testing	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.
Lifecell International Pvt. Ltd	RCV000029474	SCV003853259	likely pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000029474	SCV004101468	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003473123	SCV004211618	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000029474	SCV004848803	pathogenic	Cystic fibrosis	2022-11-03	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000029474	SCV002583259	pathogenic	Cystic fibrosis	2022-01-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734530	SCV005362512	pathogenic	CFTR-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The CFTR c.1367T>C variant is predicted to result in the amino acid substitution p.Val456Ala. This variant has been reported in the compound heterozygous and homozygous state in several patients with cystic fibrosis (McCormick et al. 2002. PubMed ID: 12357328; Uppaluri et al. 2012. PubMed ID: 22395041; Masica et al. 2015. PubMed ID: 25489051). In vitro functional studies showed that this variant resulted in significantly decreased function of CFTR (~4.1% of control) (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.16% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.