rs1800123

chr7-117627712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000492.4(CFTR):c.3659C>T(p.Thr1220Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9
• Conservation: PhyloP100: -0.302

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 67 pathogenic changes around while only 7 benign (91%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25415435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3659C>T	p.Thr1220Ile	missense_variant	22/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3659C>T	p.Thr1220Ile	missense_variant	22/27	1	NM_000492.4	P2
	ENST00000456270.1	n.66-11372G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152126 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: 0.00154

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000999 AC: 25 AN: 250156 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000763

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461024 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 726832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000958

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2022	The p.T1220I variant (also known as c.3659C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3659. The threonine at codon 1220 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a 60 year old woman with a 10 year history of chronic lung disease (Ghanem N et al. Genomics. 1994;21(2):434-6) and in a 13 year old with gastrointestinal problems, elevated sweat chloride, and pancreatic sufficiency (Onay T et al. Hum Genet. 1998;102(2):224-30); however, a second disease-causing variant in trans was not described in either case. In addition, this alteration was reported in a child with pancreatitis who was also heterozygous for disease-causing variants in PRSS1 and SPINK1 (Xiao Y et al. J. Pediatr., 2017 12;191:158-163.e3). This amino acid position is poorly conserved in available vertebrate species, and I is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1220 of the CFTR protein (p.Thr1220Ile). This variant is present in population databases (rs1800123, gnomAD 0.09%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 7522211, 9272738, 9521595, 29173301, 32777524). ClinVar contains an entry for this variant (Variation ID: 7214). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 1994	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 28, 2018	- -
Uncertain significance, 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: PM2_SUP, PM3, PP4, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 11, 2020	The CFTR c.3659C>T; p.Thr1220Ile variant (rs1800123) is reported in the literature in individuals with a clinical diagnosis of cystic fibrosis or asthma (Ghanem 1994, Lazaro 1999, Onay 1998, Xiao 2017). This variant is also reported in ClinVar (Variation ID: 7214). This variant is found in the East Asian population with an allele frequency of 0.085% (17/19,904 alleles) in the Genome Aggregation Database. The threonine at codon 1220 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.40). Given the lack of clinical and functional data, the significance of the p.Thr1220Ile variant is uncertain at this time. References: Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994. 21(2):434-6. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999. 14(6):510-9. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998. 102(2):224-30. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 02, 2024

Variant summary: CFTR c.3659C>T (p.Thr1220Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.3659C>T has been reported in the literature in individuals affected with CFTR-related conditions without strong evidence of causality (Ghanem_1994, Lazaro_1999, Onay_1998, Bozdogan_2021, Li_2022, Luo_2021, Xiao_2017, Fujita_2022, Qiao_2018, Ni_2022). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7522211, 18716917, 9521595, 12651880, 9272738, 10571949, 26471113, 29173301, 33572515, 32777524, 35313924, 34931337, 35387941, 30060175). ClinVar contains an entry for this variant (Variation ID: 7214). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

The CFTR c.3659C>T variant is predicted to result in the amino acid substitution p.Thr1220Ile. This variant was detected in the compound heterozygous state in an individual with uncharacterized bronchopathy (Ghanem et al. 1994. PubMed ID: 7522211), and in the heterozygous state in a patient with gastrointestinal problems and a sweat test score of 75 mEq/l, a patient with asthma, and in a patient with pancreatitis alongside variants in the SPINK1 and PRSS1 genes (Onay et al. 1998. PubMed ID: 9521595; Lázaro et al. 1999. PubMed ID: 10571949; and Xiao et al. 2017. PubMed ID: 29173301, respectively). This variant is reported in 0.085% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117267766-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	0.16
Dann	Benign	0.48
DEOGEN2	Uncertain	0.69	D;.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.81	L;.;.;.;.
MutationTaster	Benign	0.00023	A;A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;.;.;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.58	T;.;.;T;.
Sift4G	Benign	0.30	T;.;.;T;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.15
MVP		0.71
MPC		0.0039
ClinPred		0.0058	T
GERP RS		-4.4
Varity_R		0.16
gMVP		0.57

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: rs1800123; hg19: chr7-117267766;