rs1800110

chr7-117603774-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000492.4(CFTR):c.2900T>C(p.Leu967Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L967L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:21
• Conservation: PhyloP100: 4.04

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 Uncertain_significance. Variant got 4 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, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117603774-T-C is Pathogenic according to our data. Variant chr7-117603774-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219537.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=15, Likely_pathogenic=4, Pathogenic=1}. Variant chr7-117603774-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13665617).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2900T>C	p.Leu967Ser	missense_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2900T>C	p.Leu967Ser	missense_variant	17/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000721 AC: 181 AN: 251214 Hom.: 0 AF XY: 0.000641 AC XY: 87 AN XY: 135790

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00138 AC: 2022 AN: 1461496 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 974 AN XY: 727054

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00123

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: 0.00167

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74498

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:9

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 27, 2020	The CFTR c.2900T>C; p.Leu967Ser variant (rs1800110) is reported in the literature in multiple individuals affected with CFTR-related disorders, including some with a pathogenic variant in trans (Bishop 2005, Cohn 2005, Masson 2013, Wang 2000). This variant is observed at a higher frequency in individuals diagnosed with pancreatitis compared to unaffected individuals (odds ratio >5, p<0.05) (LaRusch 2014). The p.Leu967Ser variant is reported in ClinVar (Variation ID: 219537), and it is found in the general population with an overall allele frequency of 0.07% (199/282620 alleles) in the Genome Aggregation Database. The leucine at residue 967 is moderately conserved, and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays suggest this variant has a modest or no effect on chloride channel activity, but exhibits decreased bicarbonate transport (LaRusch 2014, Raraigh 2018). Based on available information, this variant is not expected to cause classic cystic fibrosis, but is considered to be pathogenic-mild for CFTR-related disorders. References: Bishop MD et al. The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. Hum Genet. 2005 Dec;118(3-4):372-81. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. 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. 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 8(8):e73522. 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. Wang X et al. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA. 2000 Oct 11;284(14):1814-9. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2022	PM2, PM3_strong -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	CFTR: PM3, PM2:Supporting, PS3:Supporting, PS4:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 05, 2023	This variant has been reported, alone or with a CF causing mutation, in patients with atypical presentations including oligospermia and idiopathic pancreatitis (PMIDs: 31088717 (2019), 29589582 (2017), 25033378 (2014), 23951356 (2013), 21520337 (2011), 10970190 (2000)). It has also been reported in individuals with CF or CF-like symptoms, including asthma and allergic bronchopulmonary aspergillosis (ABPA) (PMIDs: 33768849 (2021), 34782259 (2021)). In addition, this variant occurring with a second pathogenic CFTR variant has not been associated with pancreatic insufficiency or persistent Pseudomonas aeruginosa colonization (PMID: 27214204 (2016), 32784480 (2020)). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2017	The L967S variant in the CFTR gene has been reported previously in association with pancreatitis, rhinosinusitis, and nonclassic cystic fibrosis, in affected individuals who were either heterozygous for the L967S variant and no second CFTR variant, or who were heterozygous for the L967S variant and a second CFTR variant (Wang et al., 2000; Groman et al., 2002; Bishop et al., 2005; LaRusch et al., 2014). The L967S variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L967S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies show L967S has normal chloride, but selectively alters the bicarbonate permeation of the CFTR channel (LaRusch et al., 2014). We interpret L967S as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2018	- -

Cystic fibrosis Pathogenic:4 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2022	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 967 of the CFTR protein (p.Leu967Ser). This variant is present in population databases (rs1800110, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with acute recurrent pancreatitis without lung disease, hypertrypsinemia without lung disease, idiopathic chronic pancreatitis, and/or suspected cystic fibrosis (PMID: 10970190, 12167682, 15858154, 16134171, 16193325, 21499205, 21520337, 23951356, 24586523, 25033378, 33768849). ClinVar contains an entry for this variant (Variation ID: 219537). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2023	The p.L967S variant (also known as c.2900T>C), located in coding exon 17 of the CFTR gene, results from a T to C substitution at nucleotide position 2900. The leucine at codon 967 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in individuals with a second known pathogenic mutation and varying clinical presentations including: cystic fibrosis (CF), transient neonatal hypertrypsinemia, and non-classic CF; however, the phase of the alterations was not confirmed (Claustres M et al. Hum Mol Genet. 1993; 2(8):1209-1213; Boyne J et al. J Med Genet. 2000;37(7):543-547; Groman JD et al. N Engl J Med. 2002;347(6):401-407; Choi P et al. Clin Case Rep, 2021 Mar;9:1379-1382). Several studies have reported this alteration in individuals with pancreatitis, some with additional alterations in SPINK1 and/or CFTR (Audrezet MP et al. Eur J Hum Genet. 2002;10(2):100-106; Cohn JA et al. Hum Mutat. 2005;26(4):303-307; Bishop MD et al. Hum Genet. 2005;118(3-4):372-381; Masson et al. PLoS ONE 2013; 8(8):e73522; LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). One functional study showed that this alteration results in normal protein folding, glycosylation, and chloride channel activities, but HEK 293T cells expressing p.L967S have significantly altered bicarbonate permeability and conductance compared to wild-type (p<0.01) (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). In CFBE cells, chloride conductance for this variant was 74% of wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). The p.L967S alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 29, 2018). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 24, 2021	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 29, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 14, 2023	The CFTR c.2900T>C (p.Leu967Ser) variant has been reported in patients with chronic rhinosinusitis, chronic pancreatitis, or nonclassical cystic fibrosis (Bishop MD et al., PMID: 16193325; Cohen JA et al., PMID: 16134171; Groman JD et al., PMID: 12167682; LaRusch J et al., PMID: 25033378; Lucidi V et al., PMID: 21499205; Masson E et al., PMID: 23951356; Schrijver I et al., PMI: 15858154; Wang X et al., PMID: 11025834; Zietkiewicz E et al., PMID: 24586523). The majority of cases were compound heterozygous for the variant and a second variant confirmed in trans. Functional studies by one group demonstrated that p.Leu967Ser maintained 74% of CFTR function (Raraigh KS et al,. PMID: 29805046). LaRusch and colleagues showed that the variant does not impact CFTR expression, stability or chloride levels. Furthermore, they demonstrated that this and other variants not associated with typical CF alter the WNK1-SPAK activation pathway, changing CFTR permeability from a chloride to bicarbonate-preferring channel (LaRusch J et al., PMID: 25033378), indicative of an alternate disease mechanism. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.10% in the European-Non-Finnish population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to CFTR function. This variant has been reported as a variant with varying clinical consequences in the CFTR2 database (http://cftr2.org). The variant has been reported in the ClinVar database as a pathogenic variant by one submitter, likely pathogenic by three submitters and a variant of uncertain significance by 17 submitters (ClinVar Variation ID: 219537). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jul 31, 2020	Criteria Codes: PM3_VStr PM2 -

CFTR-related disorder Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 28, 2023	The CFTR c.2900T>C variant is predicted to result in the amino acid substitution p.Leu967Ser. This variant has been reported in the compound heterozygous state in individuals with hypertrypsinemia (Boyne et al. 2000. PubMed ID: 10970190) and acute recurrent pancreatitis (Lucidi et al. 2011. PubMed ID: 21499205). This variant in the compound heterozygous or heterozygous state has also been found in individuals with chronic pancreatitis (see for example Steiner et al. 2011. PubMed ID: 21520337; Masson et al. 2013. PubMed ID: 23951356; LaRusch et al. 2014. PubMed ID: 25033378) as well as individuals with suspected cystic fibrosis (see for example Schrijver et al. 2005. PubMed ID: 15858154; Ziętkiewicz et al. 2014. PubMed ID: 24586523). However, this variant has also been reported not to be causative for cystic fibrosis (Wang et al. 2000. PubMed ID: 11025834). Functional studies showed that this variant possesses ~74.4% of wildtype CFTR activity (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/219537). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 29, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 19, 2024

Variant summary: CFTR c.2900T>C (p.Leu967Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 255940 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00072 vs 0.013), allowing no conclusion about variant significance. c.2900T>C has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, non-classic CF, pancreatitis, and in a fetus with bowel anomalies. Several patients with pancreatitis were also found to carry another variant in CFTR or in other genes such as SPINK1, typically N34S, which is a known risk variant for pancreatitis. This variant also co-occurred in cis with another pathogenic variant in the CFTR gene in a fetus who had a compound heterozygous genotype [p.Phe508del/c.3191_3192ins16 (de Becdelivre_2011)]suggesting that L967S was not causative in this patient and is unlikely to be pathogenic in the autosomal recessive Mendelian inheritance pattern. In contrast, case-control studies (example, LaRusch_2014) suggest that L967S may increase the risk of developing pancreatitis (odds ratio=6.87 (p-value 0.002); with further increased odds ratio of 11.17 (p-value 0.014) in patients with co-occurring SPINK1 variant N34S. An in vitro functional study reported that this missense change does not affect CFTR expression, stability, or chloride conductance, but has a mild effect on bicarbonate permeability and conductance with WNK1-SPAK activation in cell culture (LaRusch_2014). Another study indicated that L967S maintained approximately 74% of wild-type function (Raraigh_2018). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 7691344, 15858154, 16134171, 21184098, 21520337, 16193325, 11025834, 11938439, 21499205, 23951356, 24451227, 24586523, 25824995, 25963003, 18195584, 28544683, 29805046, 25033378, 29589582, 31088717, 32784480, 33946859, 33768849, 34996830). ClinVar contains an entry for this variant (Variation ID: 219537). The CFTR2 database reports this variant as having varying consequences, indicating that clinical criteria alone should be used to diagnose individuals with this variant with CFTR-related phenotypes. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Infertility disorder Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

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Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Feb 09, 2022

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Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 22, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.3	L;.;.;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.46	N;.;.;N;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.96	D;.;.;.;.
Vest4		0.82
MVP		1.0
MPC		0.0064
ClinPred		0.045	T
GERP RS		4.7
Varity_R		0.24
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: rs1800110; hg19: chr7-117243828;