7-117664780-G-T

Position:

chr7-117664780-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000492.4(CFTR):c.4056G>T(p.Gln1352His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5B:1

Conservation

PhyloP100: 2.15

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 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, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4056G>T	p.Gln1352His	missense_variant	25/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.4056G>T	p.Gln1352His	missense_variant	25/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000478

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251226

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.000478

Alfa

AF:

0.0000296

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 23, 2020	The CFTR c.4056G>T; p.Gln1352His variant (rs113857788), and another variant resulting in the same amino acid change (c.4056G>C; p.Gln1352His), are reported in the literature in multiple individuals affected with CFTR-related disorders such as pancreatitis and congenital bilateral absence of the vas deferens (Anzai 2003, Claustres 2017, Lee 2003, Ratbi 2007). The p.Gln1352His variant is also reported to be enriched in Asian pancreatitis patients compared to unaffected individuals (Claustres 2005, Kondo 2015, Nakano 2015). Expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). The c.4056G>T; p.Gln1352His variant is reported in ClinVar (Variation ID: 35882), and is found in the general population with an overall allele frequency of 0.006% (17/282620 alleles) in the Genome Aggregation Database. The glutamine at residue 1352 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, this variant is considered to be mildly pathogenic. References: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003; 2(1):14-8. Claustres M et al. Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online. 2005 Jan;10(1):14-41. Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. Lee J et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003; 12(18):2321-32. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007; 22(5):1285-91. -

Cystic fibrosis

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2023	The p.Q1352H variant (also known as c.4056G>T) is located in coding exon 25 of the CFTR gene. This alteration results from a G to T substitution at nucleotide position 4056. The glutamine at codon 1352 is replaced by histidine, an amino acid with highly similar properties. This same amino acid change has been reported in the literature as the result of a different underlying nucleotide substitution (c.4056G>C). The amino acid change was reported in 5 of 19 males with congenital bilateral absence of the vas deferens (CBAVD), one of which was a compound heterozygote for the p.W216* pathogenic mutation (Anzai C et al. 2003; J Cystic Fibrosis.; 2:14-18). The p.Q1352H substitution was found to be significantly associated with bronchiectasis in a small Korean population. In addition, in vitro functional studies showed that this amino acid substitution results in a 70-80% reduction in the expression of the mature glycosylated CFTR protein and in chloride channel activity (Lee JH et al. Hum Mol Gen. 2003; 12(18):2321-2332). Other studies report an association with chronic pancreatitis or pulmonary disease, but these studies failed to control for confounding factors, analyze other potential genes, or reach statistical significance (Fujiki K et al. J Med Genet. 2004;41(5):e55; Ngiam N et al. J Cyst Fibrosis. 2006;5(3):159-164). A recent study found a strong association of this variant with chronic pancreatitis; of 193 patients tested, 10% carried this variant (p = 0.005) (Nakano et al 2015; Dig Dis Sci; 60(5):1297-307). This amino acid position is highly conserved on sequence alignment. This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on available evidence, this variant is unlikely to be causative of classic CF; however, its clinical contribution to the development of a CFTR-related disorder in specific populations is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

Hereditary pancreatitis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

May 24, 2021

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 12, 2024

Variant summary: CFTR c.4056G>T (p.Gln1352His) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 6e-05 in 251226 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (6e-05 vs 0.013), allowing no conclusion about variant significance. c.4056G>T has been reported in at least one homozygous patient with CBAVD (e.g., Claustres_2017). Another variant at this position, c.4056G>C (legacy c.4188 G>C), which encodes the same p.Gln1352His amino acid change, has been reported in the literature as well. The Gln1352His missense variant (in many cases without specifying nucleotide substitution) have been reported in individuals affected with multiple CFTR-Related Diseases, including chronic pancreatitis (e.g., Fujiki_2004, Lee_2003, Lee_2005, Keiles_2006, Nakano_2015, Cho_2016), Congenital Bilateral Absence of the Vas Deferens (CBAVD; e.g., Braekeleer_1996, Dork_1997, Danziger_2004, Ratbi_2007, Steiner_2011, Claustres_2017), and bronchiecstasis (e.g., Lee_2003). In at least several of these patients, a second pathogenic mutation in CFTR was identified, while in others, a second variant was not found. The variant has also been reported in individuals affected by severe asthma (e.g., Ngiam_2006), primary sclerosing cholangitis (e.g., Pall_2007), sarcoidosis (e.g., Makrythanasis_2010), impaired male fertility (e.g., Rudnik-Shoneborn_2021) and azoospermia (e.g., Ooi_2014). These reports do not contain co-segregation information definitively associating the variant with disease, however several case-control studies report a significant over-representation of the Gln1352His variant in individuals affected with chronic pancreatitis phenotypes (e.g., Lee_2003, Fujuiki_2004, Nakano_2015). The variant has also been reported as part of a complex allele with p.I807M in the compound heterozygous state with known pathogenic alleles in asymptomatic individuals (e.g., Claustres_2017). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that variant results in defective protein expression and channel kinetics (e.g., Lee_2003). Collectively, the currently available information suggests that the Gln1352His variants could be associated with mild CFTR-related phenotypes, however further evidence such as co-segregation studies are needed to conclusively establish association with these CFTR-related diseases. The following publications have been ascertained in the context of this evaluation (PMID: 15716623, 22324837, 16596947, 32025909, 9239681, 27578509, 28603918, 15705292, 14998948, 9272157, 15121783, 20021716, 20052366, 28456595, 33502066, 17003641, 15829248, 12952861, 25880441, 20722470, 22664493, 31808782, 25492507, 15645635, 16678503, 27324553, 20558957, 24697796, 17719933, 25735457, 29805046, 17329263, 33374015, 18304229, 26708955, 21520337, 31940241, 16435054, 19812525, 29216686). ClinVar contains an entry for this variant (Variation ID: 35882). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CFTR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2023

The CFTR c.4056G>T variant is predicted to result in the amino acid substitution p.Gln1352His. This variant has been reported in the heterozygous state in patients with congenital bilateral absence of vas deferens (https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.4056G>T; Table 2 and 4 in Claustres. 2017. PubMed ID: 28603918). This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117304834-G-T). A different nucleotide change that results in the same amino acid change (c.4056G>C, p.Gln1352His) has been reported on extensively in the literature. The c.4056G>C, p.Gln1352His variant has been reported in patients with several different phenotypes including asthma, alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, azoospermic males, and bronchiectasis (Cho. 2016. PubMed ID: 27578509; Gallati. 2009. PubMed ID: 20021716; Kondo. 2015. PubMed ID: 26089335; Pall. 2007. PubMed ID: 17719933). The c.4056G>C (p.Gln1352His) variant has been found at higher rates in Asian patients with pancreatitis (12.3%) compared to unaffected controls (3.7%) (Fujiki et al. 2004. PubMed ID: 15121783). However, the majority of these studies were conducted in Eastern Asian population cohorts where the c.4056G>C variant is found at a higher allele frequency (~1.3% in East Asians, http://gnomad.broadinstitute.org/variant/7-117304834-G-C). Functional studies in CHO cell lines indicate the p.Gln1352His change decreases CFTR protein expression and chloride channel function (Lee et al. 2003. PubMed ID: 12952861; Fujiki. 2004. PubMed ID: 15121783; Ngiam. 2006. PubMed ID: 16678503). However, no family studies have been conducted to determine if the c.4056G>C variant segregates with disease in individual families and to our knowledge, no homozygous c.4056G>C individuals have been reported with a CFTR-related disorder. The c.4056G>T has conflicting interpretations in ClinVar ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/35882). In summary, it is possible that the p.Gln1352His variant is associated with mild CFTR-related phenotypes or exhibits reduced penetrance . However, without additional conclusive evidence, the clinical significance of this variant remains uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.99

MutPred

0.99

Gain of catalytic residue at M1354 (P = 0.0865);.;.;

MVP

1.0

MPC

0.018

ClinPred

0.94

GERP RS

3.6

Varity_R

0.94

gMVP

0.96

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