rs397508783

chr7-117535363-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★★). Synonymous variant affecting the same amino acid position (i.e. V232V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 5.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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	UniProt
CFTR	NM_000492.4	c.695T>A	p.Val232Asp	missense_variant	6/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.695T>A	p.Val232Asp	missense_variant	6/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

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: 6 AN: 251400 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

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: 30 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727236

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: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

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: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -
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, 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	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 25, 2015	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2022	PM3_very_strong, PS3 -
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. -

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 disorders 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 disorders 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

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	D;.;.;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.3	L;.;.;.;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.37	T
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	D
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

Other links and lift over

dbSNP: rs397508783; hg19: chr7-117175417;