rs397508783

Positions:

chr7-117535363-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.695T>A(p.Val232Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 5.78

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 26) in uniprot entity CFTR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 7-117535363-T-A is Pathogenic according to our data. Variant chr7-117535363-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 54041.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535363-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.695T>A	p.Val232Asp	missense_variant	6/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.695T>A	p.Val232Asp	missense_variant	6/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251400

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

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, PM2_SUP, PM3_VSTR, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 12, 2020	Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 03, 2021	The p.V232D pathogenic mutation (also known as c.695T>A), located in coding exon 6 of the CFTR gene, results from a T to A substitution at nucleotide position 695. The valine at codon 232 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This mutation has been described in a Brazilian cystic fibrosis (CF) patient with pancreatic sufficiency, who also carried the p.R334W mutation (Bernardino AL et al, Genet. Test. 2000 ; 4(1):69-74). It was also reported in Spanish CF patients (Casals T et al, Hum. Genet. 1997 Dec; 101(3):365-70) as well as in a French patient with idiopathic chronic pancreatitis who also carried an p.M348K alteration in CFTR but no alterations in PRSS1, SPINK1 or CTRC (Masson E et al, PLoS ONE 2013 ; 8(8):e73522). It has also been observed in the homozygous state in a man who presented with congenital bilateral absence of the vas deferens (CBAVD) (Larriba S et al, Hum. Mol. Genet. 1998 Oct; 7(11):1739-43). Rectal biopsy specimen from a CF patient who carried this mutation and p.F508del showed residual chloride secretion (Hirtz S et al, Gastroenterology 2004 Oct; 127(4):1085-95). In vitro studies have suggested that this mutation leads to impaired CFTR protein maturation and reduced channel activity (Loo TW et al, Biochem. Pharmacol. 2014 Mar; 88(1):46-57; Hirtz S et al, Gastroenterology 2004 Oct; 127(4):1085-95; Caldwell RA et al, Am. J. Physiol. Lung Cell Mol. Physiol. 2011 Sep; 301(3):L346-52). Based on the available evidence, p.V232D is classified as a pathogenic mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 232 of the CFTR protein (p.Val232Asp). This variant is present in population databases (rs397508783, gnomAD 0.009%). This missense change has been observed 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). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 2441227, 11427889, 17516627, 17949679, 19625452, 21909392, 21996038). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 13, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	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, Fernandez-Lorenzo 2018, Hirtz 2004). However, this variant has also been 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 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 moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.720). 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 pathogenic, with varying clinical consequences. References: Link to CFTR2 database: https://cftr2.org/mutation/scientific/pi/V232D Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. PMID: 10794365. 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. PMID: 21642448. 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. PMID: 9439669. 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. PMID: 10875853. 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. PMID: 18456578. 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. PMID: 23670503. Fernandez-Lorenzo AE et al. V232D mutation in patients with cystic fibrosis: Not so rare, not so mild. Medicine (Baltimore). 2018 Jul;97(28):e11397. PMID: 29995784. 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. PMID: 15480987. 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. PMID: 24412276. 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. PMID: 23951356. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2022	PM3_very_strong, PS3 -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 26, 2018

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. -

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;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 23, 2019

- -

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

Jul 31, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.93

D;.;.;D;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

1.3

L;.;.;.;L

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-4.6

D;.;.;D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.74

P;.;.;.;.

Vest4

0.93

MutPred

0.93

Loss of MoRF binding (P = 0.1959);Loss of MoRF binding (P = 0.1959);Loss of MoRF binding (P = 0.1959);.;Loss of MoRF binding (P = 0.1959);

MVP

1.0

MPC

0.0068

ClinPred

0.89

GERP RS

5.4

Varity_R

0.95

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over