rs139468767

chr7-117592020-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.1853T>C(p.Ile618Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,593,202 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.38

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 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 7-117592020-T-C is Pathogenic according to our data. Variant chr7-117592020-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117592020-T-C is described in Lovd as [Pathogenic]. Variant chr7-117592020-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1853T>C	p.Ile618Thr	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1853T>C	p.Ile618Thr	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000217 AC: 5 AN: 230522 Hom.: 0 AF XY: 0.0000240 AC XY: 3 AN XY: 124744

Gnomad AFR exome AF: 0.000322

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000694 AC: 10 AN: 1441010 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 715986

Gnomad4 AFR exome AF: 0.000219

Gnomad4 AMR exome AF: 0.00

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: 9.04e-7

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74332

Gnomad4 AFR AF: 0.000507

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the CFTR protein (p.Ile618Thr). This variant is present in population databases (rs139468767, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9150159, 23857699; external communication, http//www.genet.sickkids.on.ca/). This variant is also known as c.1985T>C. ClinVar contains an entry for this variant (Variation ID: 53404). 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: 9736778, 9822639). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2024	The p.I618T variant (also known as c.1853T>C), located in coding exon 14 of the CFTR gene, results from a T to C substitution at nucleotide position 1853. The isoleucine at codon 618 is replaced by threonine, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this variant was identified in one individual in conjunction with p.G542*; however, specific clinical details and the phase of the variants were not provided (Gonçalves AC et al. J Pediatr (Rio J), 2018 May;pii: S0021-7557(17)31053-7). Studies have demonstrated that this variant results in decreased chloride channel activity and abnormal protein processing (Pasyk EA et al. J. Biol. Chem., 1998 Nov;273:31759-64; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This variant 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 September 29, 2020). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 26, 2023	PS3, PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 3.8e-05 in 262104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (3.8e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.1853T>C, has been reported in the literature in compound heterozygosity with p.F508del or p.G542X in at-least three individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012, Faria_2017). These data indicate that the variant may be associated with disease although multiple publications reporting the same patients confound distinct ascertainment (example, Vankeerberghen_1998, Marson_2012A, Marson_2013, Guimbellot_2017, Goncalves_2018, Pereira_2019, Faria_2017). Additionally, this variant has been observed in compound heterozygosity with other classic CFTR mutations such as p.A559T (c.1675G>A), p.F508del (c.1521_1523delCTT) and p.Ser1255X (c.3764C>A) in at-least three patients (a pair of sibs and two other distinct patients) sequenced for the CFTR gene at our laboratory. Detailed clinical information was available on one of these patients who was confirmed to have a known diagnosis of pancreatically insufficient CF with elevated sweat chloride levels, positivity for CF pathogens, severe baseline lung disease, and sinusitis. As the compound heterozygous genotypes observed in our laboratory are distinct (p.A559T and p.Ser1255X) from those reported in the literature, these data indicate that the variant is likely to be associated with disease (ACMG PP4). One publication, Pasyk_1998, reported this variant exhibits <50% of normal activity as chloride channel (ACMG PS3) while another publication, Vankeerberghen_1998, not providing primary data, reported this variant as resulting in abnormal processing leading to no or minimal functional CFTR proteins appearing at the cell membranes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a complete consensus (Likely Pathogenic, n=5, Pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 01, 2019	This CFTR variant (rs139468767) has been previously reported and is rare in large population datasets (gnomAD: 10/261916 total alleles; 0.003818%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as pathogenic and a third as a variant of uncertain clinical significance. Independent functional studies determined that this protein does not mature into its fully glycosylated state. Additionally, if any protein is properly trafficked, it is predicted to have reduced chloride conductance. This variant is considered likely pathogenic. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 10, 2020	The CFTR c.1853T>C; p.Ile618Thr variant (rs139468767) is reported in the literature in multiple individuals affected with cystic fibrosis who also carry a pathogenic variant presumed to be on the opposite chromosome (Macek 1997, Marson 2012). This variant is reported in ClinVar (Variation ID: 53404), and is only observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 618 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show reduced cell surface expression and channel function (Pasyk 1998, Vankeerberghen 1998). Based on available information, this variant is considered to be likely pathogenic. References: Macek M et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75 percent. Am J Hum Genet. 1997 60(5):1122-7. Marson FA et al. The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis. BMC Pulm Med. 2012 Aug 8;12:41. Pasyk EA et al. A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. J Biol Chem. 1998 Nov 27;273(48):31759-64. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 7(11):1761-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 29, 2021	PP3, PM2, PM3_strong, PS3 -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 03, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;.;D;.
Sift4G	Uncertain	0.016	D;.;D;.
Polyphen		0.94	P;.;.;.
Vest4		0.88
MVP		1.0
MPC		0.0039
ClinPred		0.32	T
GERP RS		5.5
Varity_R		0.80
gMVP		0.92

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: rs139468767; hg19: chr7-117232074;