rs193922500

chr7-117548798-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):c.1367T>C(p.Val456Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000939 in 1,608,738 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V456F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:26
• Conservation: PhyloP100: 7.29

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117548797-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53236.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 7-117548798-T-C is Pathogenic according to our data. Variant chr7-117548798-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 35821.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117548798-T-C is described in Lovd as [Likely_pathogenic]. Variant chr7-117548798-T-C is described in Lovd as [Pathogenic]. Variant chr7-117548798-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1367T>C	p.Val456Ala	missense_variant	10/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.222-6259A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1367T>C	p.Val456Ala	missense_variant	10/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151720 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00250

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000204 AC: 50 AN: 244512 Hom.: 0 AF XY: 0.000317 AC XY: 42 AN XY: 132434

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.0000954 AC: 139 AN: 1456902 Hom.: 1 Cov.: 35 AF XY: 0.000150 AC XY: 109 AN XY: 724554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151836 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74182

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 20, 2021	- -
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	Centogene AG - the Rare Disease Company	Apr 30, 2020	- -
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	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, no assertion criteria provided	clinical testing	Baylor Genetics	Jan 23, 2022	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
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	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	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	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 13, 2016	- -
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. -
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. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2023	Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (Raraigh 2018); 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, 17035430, 35652053, 35857025, Conti 2023[Review], 35761057) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2019	PS3, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2023	- -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 15, 2019

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. -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Mar 09, 2018

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 26, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.82	P;.
Vest4		0.90
MutPred		0.95		Gain of disorder (P = 0.0299);.;
MVP		1.0
MPC		0.0069
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922500; hg19: chr7-117188852;