rs1800079

Positions:

chr7-117534295-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The ENST00000003084.11(CFTR):c.509G>A(p.Arg170His) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,593,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:19B:2

Conservation

PhyloP100: 7.14

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 Uncertain_significance. Variant got 0 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, 14 uncertain in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031353205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.509G>A	p.Arg170His	missense_variant	5/27	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.509G>A	p.Arg170His	missense_variant	5/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000499

AC:

125

AN:

250408

Hom.:

AF XY:

0.000472

AC XY:

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000522

AC:

752

AN:

1441552

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

353

AN XY:

718396

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00654

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000816

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000465

Gnomad4 OTH exome

AF:

0.000820

GnomAD4 genome

AF:

0.000440

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000644

Hom.:

Bravo

AF:

0.000502

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000469

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000766

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:19Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:9Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 22, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2024	The p.R170H variant (also known as c.509G>A), located in coding exon 5 of the CFTR gene, results from a G to A substitution at nucleotide position 509. The arginine at codon 170 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in 9 children with a CF-causing mutation confirmed in trans; none of the children had elevated sweat chloride levels, pancreatic insufficiency, or Pseudonomas aeruginosa colonization (Salinas DB et al. PLoS One, 2016 May;11:e0155624). However, this variant has also been detected in conjunction with a CFTR pathogenic mutation in multiple individuals with intermediate sweat chloride levels and/or CFTR-related disorders, including chronic pancreatitis and congenital bilateral absence of the vas deferens (Wei S et al. Genet. Med., 2006 Apr;8:255-8; McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8; Taulan M et al. BMC Med Genet, 2007 Apr;8:22; Ambry internal data). In an in vitro study, this variant demonstrated 150% chloride channel function, compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). In a separate study, the variant showed normal chloride function, but reduced bicarbonate permeability and conductance (LaRusch J et al. PLoS Genet, 2014 Jul;10:e1004376). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Aug 03, 2023	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.). The patient has not been seen or tested by our laboratory. Clinical diagnosis was documented in the Registry. Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PS3_SUP, PM5_STR, PP3, BP2, BS3_SUP -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The CFTR c.509G>A (p.Arg170His) missense variant has been reported in at least five studies in which it is found in several individuals with variable but generally milder presentations of CFTR-related disorders. The p.Arg170His variant was found in four individuals with congenital bilateral absence of vas deferens (CBAVD), including three compound heterozygotes and one heterozygote; in one heterozygous individual with cystic fibrosis (CF); and in five heterozygous individuals with pancreatitis (Bishop et al. 2005; Ratbi et al. 2007; Steiner et al. 2011; Krenkova et al. 2013; LaRusch et al. 2014). Two additional individuals with CBAVD reported in the Cystic Fibrosis Mutation Database were compound heterozygous for the p.Arg170His variant and a second well-known pathogenic variant (http://www.genet.sickkids.on.ca/app). The p.Arg170His variant was found in a heterozygous state in two of approximately 1800 total controls from the above studies and is reported at a frequency of 0.0071 in the Ashkenazi Jewish population of the Genome Aggregation Database. Aissat et al. (2013) demonstrated that when the p.Arg170His variant is present, there is a significant increase in exon 5 skipping as compared to that observed in wild type. Recently, however, Salinas et al. (2016) and the CFTR2 database (https://www.cftr2.org/) reported nine compound heterozygous children ascertained by newborn screening who carried the p.Arg170His variant in trans with known disease-causing CFTR variants without a positive sweat chloride test, pancreatic insufficiency or P. aeruginosa colonization, confounding the clinical implications of this variant. Based on the evidence, the p.Arg170His variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:1Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2024	Described as a bicarbonate defective allele in published functional studies: decrease of CFTR bicarbonate conductance and altered bicarbonate permeation of the CFTR channel while not affecting the chloride channel (PMID: 25033378, 29805046); Observed with a pathogenic CFTR variant, phase unknown, in published literature in individuals with cystic fibrosis and/or congenital absence of the vas deferens but also in unaffected individuals (PMID: 27728908, 27214204, 16189704, 21520337, 16617247, 17448246); Observed in published literature in individuals with pancreatitis (PMID: 21520337, 16189704, 25033378); In silico analysis indicates that this missense variant does not alter protein structure/function; Classified as a non CF-causing variant in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 27171515, 26847993, 28502372, 17329263, 28456595, 20021716, 29805046, 23276700, 27214204, 28194692, 27104957, 10746558, 16193325, 16244288, 17662673, 20059485, 21388895, 26708955, 27728908, 18716917, 29589582, 28465863, 15536480, 16251901, 26277102, 23420618, 25033378, 21520337, 16617247, 16189704, 17448246, 32143663, 34426522, 34525262, 34860163, 34405919, 34996830, 32508047, 35753512) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	The CFTR c.509G>A; p.Arg170His variant (rs1800079) is reported in the literature in the compound heterozygous state in multiple individuals affected with chronic pancreatitis or other CFTR-related disorders (Gallati 2009, LaRusch 2014, Palermo 2016, Steiner 2011, Wei 2006). Functional analyses of the variant show a slight increase in exon 5 skipping (Aissat 2013), but mature protein expression levels and chloride transport activity similar to wildtype (LaRusch 2014). However, the variant protein exhibits impaired bicarbonate transport, which is also observed for other CFTR variants enriched in pancreatitis patients (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 53983), and is found in the Ashkenazi Jewish population with an allele frequency of 0.72% (75/10358 alleles) in the Genome Aggregation Database. The arginine at residue 170 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.829). Additionally, other variants at this codon (c.508C>T; p.Arg170Cys, c.508C>G; p.Arg170Gly) have been reported in individuals with CFTR-related diseases (Sharma 2014, see link to cystic fibrosis mutation database). Based on available information, while the p.Arg170His variant is not predicted to result in cystic fibrosis, it is considered to be mildly pathogenic for CFTR-related disorders. References: Link to cystic fibrosis mutation database: http://genet.sickkids.on.ca/cftr/Home.html Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 34(6):873-81. PMID: 23420618. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. PMID: 20021716. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. PMID: 25033378. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. PMID: 27171515. Sharma H et al. Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers. Mol Hum Reprod. 2014 Sep;20(9):827-35. PMID: 24958810. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 32(8):912-20. PMID: 21520337. Wei S et al. Cystic Fibrosis testing among Arab-Americans. Genet Med. 2006 8(4):255-8. PMID: 16617247. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2023	The CFTR c.509G>A (p.Arg170His) variant has been reported in the published literature along with other CF variants in individuals with Cystic Fibrosis (PMID: 32143663 (2020), 33577586 (2021), 23276700 (2013), 21520337 (2011)). This variant is also reported in individuals with Cystic Fibrosis Related Disorder (CFRD) including CBAVD (congenital absence of the vas deferens) (PMID: 17329263 (2007), 16189704 (2005)), pancreatitis (PMID: 27171515 (2016), 25033378 (2014), 16189704 (2005)) and azoospermia (PMID: 20021716 (2009)). A functional study reported that this variant demonstrated chloride conductance similar to wild type CFTR protein (PMID: 29805046 (2018)). Another functional study found normal chloride function but abnormal bicarbonate permeability and conductance (PMID: 25033378 (2014)). The frequency of this variant in the general population, 0.0072 (75/10358 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 20, 2022	PP3, PM2 -

CFTR-related disorder

Pathogenic:2Uncertain:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 22, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Nov 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 07, 2024	The CFTR c.509G>A variant is predicted to result in the amino acid substitution p.Arg170His. This variant has been reported in association with cystic fibrosis (Alibakhshi et al. 2008. PubMed ID: 17662673; Baker et al. 2011. PubMed ID: 21388895; Křenková et al. 2013. PubMed ID: 23276700; Prontera et al. 2016. PubMed ID: 27728908) and CFTR-related disorders such as congenital bilateral absence of the vas deferens and/or chronic pancreatitis (McGinniss et al. 2005. PubMed ID: 16189704; Wei et al. 2006. PubMed ID: 16617247; Ratbi et al. 2007. PubMed ID: 17329263; Taulan et al. 2007. PubMed ID: 17448246; de Cid et al. 2010. PubMed ID: 19812525; Steiner et al. 2011. PubMed ID: 21520337; LaRusch et al. 2014. PubMed ID: 25033378; Palermo et al. 2016. PubMed ID: 27171515). However, this variant has also been reported in unaffected control subjects (Steiner et al. 2011. PubMed ID: 21520337) and patients carrying a second CF-causing variant with a benign clinical course, or features that were not consistent with a diagnosis of cystic fibrosis (Salinas et al. 2016. PubMed ID: 27214204; https://cftr2.org/mutation/general/R170H/). Functional studies indicate that the p.Arg170His variant reduces bicarbonate conductance in vitro, but does not impact protein folding, glycosylation, or chloride channel activities (LaRusch et al. 2014. PubMed ID: 25033378). This variant is reported in 0.72% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. While it is possible that the c.509G>A (p.Arg170His) variant may contribute to CFTR-related disorders with incomplete penetrance, at this time we interpret it to be a variant of uncertain significance due to conflicting genetic and functional data. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 18, 2023

Criteria applied: PM5_STR,PM3,PS3_SUP,PP3,BP2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 02, 2024

Variant summary: CFTR c.509G>A (p.Arg170His) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00051 in 254598 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (0.00051 vs 0.013), allowing no conclusion about variant significance. The variant, c.509G>A, has been reported in the literature and locus specific database (UMD) in compound heterozygosity, in most cases with a CF-causing variant, in multiple CBAVD patients, who had no classic cystic fibrosis (CF) phenotype (Wei_2006, Taulan_2007, Steiner_2011, McGinniss_2005, Ratbi_2007) and in infants (also in combination with a CF-causing variant) who were undergoing newborn screening, and had no CF phenotype (Salinas_2016). The variant was also reported in a CF patient with another pathogenic variant (Combret_2021), however, in another CF-case a co-occurrence with a homozygous pathogenic variant has been reported (CFTR c.988G>T, p.Gly330Ter; in Lascano-Vaca_2020), providing supporting evidence for a non-causative role. In addition, the variant was reported in heterozygosity, i.e. without a second variant, in a few patients diagnosed with idiopathic chronic pancreatitis (ICP) (Bishop_2005, Steiner_2011) or cystic fibrosis (CF) (Alibakhshi_2008, Baker_2011, Krenkova_2012), but, it was also found in several controls (Bombieri_2000, Steiner_2011, Modiano_2005, Pompei_2006). These data indicate that the variant may be associated with CBAVD, but allow no conclusion about its association with classic CF. Publications also reported experimental evidence evaluating an impact on protein function. One study demonstrated that while the p.Arg170His protein had normal folding, glycosylation, chloride channel, bicarbonate permeability and bicarbonate conductance activities, it had impaired bicarbonate permeability in the setting of WNK1 and SPAK co-expression at low chloride ion levels (LaRusch_2014). Authors suggested that the selective bicarbonate defect in CFTR channel function might affect those organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens), causing associated symptoms (e.g. increased risk for pancreatitis, rhinosinusitis and male infertility), but not typical CF. Another publication assessed chloride channel function in vitro by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR, and found that cells expressing the variant protein had similar chloride channel function to the wild-type (Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 17662673, 21388895, 16244288, 16193325, 10746558, 33577586, 18685558, 20059485, 20021716, 18716917, 33922413, 29589582, 23276700, 25033378, 32143663, 33341408, 16189704, 15536480, 32387800, 16251901, 29805046, 17329263, 27214204, 21520337, 17448246, 16617247, UMD database).ClinVar contains an entry for this variant (Variation ID: 53983). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Dec 08, 2021

- -

Chronic pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 30, 2023

This sequence change in CFTR is predicted to replace arginine with histidine at codon 170, p.(Arg170His). The arginine residue is highly conserved (92/95 vertebrates, UCSC), and is located in exon 5 within the ABC transporter transmembrane region. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (42/128,708 alleles) in the European (non-Finnish) population, which is consistent with autosomal recessive cystic fibrosis (CF), but higher than expected for autosomal dominant hereditary pancreatitis. This variant has been observed in nine compound heterozygous children along with a known pathogenic CFTR variant who were detected by newborn screening, with no objective features of cystic fibrosis as defined by pancreatic insufficiency, positive chloride sweat test or lung pseudomonas colonisation (PMID: 27214204). However, this variant has been reported in at least sixteen heterozygous probands (both heterozygotes and compound heterozygotes with a known pathogenic CFTR variant- phase unknown in all but two individuals of the latter group where it is in trans) meeting the criteria for a CFTR-related disorder other than cystic fibrosis, including recurrent acute pancreatitis, chronic pancreatitis or congenital bilateral absence of vas deferens (CBAVD; PMID: 16193325, 17329263, 16189704, 16617247; CFTR France variant database, https://cftr.iurc.montp.inserm.fr/cftr/). The CFTR2 variant database (https://cftr2.org/) records eleven alleles with this variant amongst 89,052 individuals, with 33% of compound heterozygote individuals with this variant and a known pathogenic CFTR variant recorded as having pancreatic insufficiency. The prevalence of the variant in affected individuals with chronic pancreatitis is significantly increased compared with the prevalence in gnomAD controls (OR = 2.6798, 95% CI 1.0594 - 6.7784), using the aggregated case figures from a meta-analysis of six studies with this variant (PMID: 36264955). This variant has been observed with the pathogenic variant (c.3846G>A, p.Trp1282Ter; ClinVar: VCV000007129.90) in an individual diagnosed with CF on a positive chloride sweat test, although the patient had relatively normal pulmonary function and performance status compared to other cystic fibrosis patients in this cohort (PMID: 33577586). The phase of the variants is unknown. Other reports exist of this variant detected in at least five individuals diagnosed with CF; however, it is unclear in these cases whether different variants may be responsible (e.g. PMID: 32143663, 21388895, 17662673), and/or the phenotype information is missing or incomplete (e.g. PMID: 27728908, 23276700). Western blot and patch clamp in vitro experiments using HEK 293T cells transfected with variant protein demonstrated normal protein expression and glycosylation along with chloride permeability, but reduced bicarbonate permeability/conductance in the presence of WNK1/SPAK, which models the bicarbonate-dependent pathophysiology of CFTR variants in the pancreas, sinuses and male reproductive tract (PMID: 25033378). This, along with other data showing normal chloride conductance in human epithelial cell lines expressing mutant protein constructs (PMID: 29805046) indicates that the impact of the variant on protein function is limited to bicarbonate conductance in specific organs (including the pancreas, but excluding the lungs). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (VUS). Following criteria are met: PP3, PS3_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.031

T;T;T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.9

L;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.7

N;.;.;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0070

D;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.90

MVP

1.0

MPC

0.0089

ClinPred

0.085

GERP RS

5.5

Varity_R

0.44

gMVP

0.87

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