rs148519623

Positions:

chr7-117536598-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000492.4(CFTR):c.794T>G(p.Met265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,607,876 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 3.89

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 9 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 7-117536598-T-G is Pathogenic according to our data. Variant chr7-117536598-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54058.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3, Pathogenic=1}. Variant chr7-117536598-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.794T>G	p.Met265Arg	missense_variant	7/27	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.794T>G	p.Met265Arg	missense_variant	7/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

245598

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132826

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1455702

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000280

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2024	Variant summary: CFTR c.794T>G (p.Met265Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245598 control chromosomes. c.794T>G has been reported in the literature as a compound heterozygous genotype with p.F508del in multiple individuals affected with features resembling Non-Classic Cystic Fibrosis ranging from CBAVD (example, Dork_1997, Goossens_2000), to pancreatic insufficiency and intermediate levels of sweat chloride (example, McCague_2019). As of now, there are multiple patients with this variant in the CFTR2 database and it was annotated as a variant with varying clinical consequences, i.e. some patients with this variant, combined with another CF-causing variant, have CF, while other patients do not have CF. Because of this variability, it is very important that clinical criteria alone be used to determine whether a person with this variant has CF. These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 6.38% of normal chloride channel conductance relative to wild type (e.g., Okiyoneda_2013, Raraigh_2018, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 17440499, 10913957, 12900515, 25735457, 26708955, 26471113, 23666117, 29805046, 30888834, 36207272, 38388235). ClinVar contains an entry for this variant (Variation ID: 54058). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2024	The p.M265R variant (also known as c.794T>G), located in coding exon 7 of the CFTR gene, results from a T to G substitution at nucleotide position 794. The methionine at codon 265 is replaced by arginine, an amino acid with similar properties. This variant was described in an individual in conjunction with p.F508del who had congenital absence of the vas deferens, recurrent infections, pancreatitis, and borderline sweat chloride levels (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). The p.M265R alteration has been reported as a variant of varying clinical consequences (VVCC) and was associated with a partial reduction in CFTR function on one assay (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 the available evidence, the clinical significance of this variant remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 265 of the CFTR protein (p.Met265Arg). This variant is present in population databases (rs148519623, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens as well as recurrent upper respiratory infections and pancreatitis (PMID: 9272157, 12900515, 30888834). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 54058). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23666117, 29805046). 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. -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2019	The CFTR c.794T>G; p.Met265Arg variant (rs148519623) reported is reported in the literature in a newborn with meconium ileus (SickKids CFTR database) and in individuals with congenital bilateral absence of vas deferens or pancreatitis (Dork 1997, Goossens 2000). At least three affected individuals were also observed to carry the pathogenic p.Phe508del variant (SickKids CFTR database, Dork 1997, Goossens 2000). The p.Met265Arg variant is also reported in seven individuals in the CFTR2 database (see link) that also carried a second pathogenic variant, of whom the majority were pancreatic-insufficient. The p.Met265Arg variant is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. In functional assays, the variant protein exhibits only 19% of wildtype CFTR chloride channel activity (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic. References: CFTR2 database: https://cftr2.org/ SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=156 Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997; 100(3-4):365-77. Goossens V et al. Clinical application of preimplantation genetic diagnosis for cystic fibrosis. Prenat Diagn. 2000 Jul;20(7):571-81. 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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 24, 2023	It has been reported in the published literature with the c.1521_1523del (p.Phe508del) variant on the opposite chromosome in a female newborn with meconium ileus, in several individuals with pancreatic insufficiency and intermediate sweat chloride (PMID: 30888834 (2019)), and in two individuals with congenital bilateral absence of vas deferens (CBAVD) (PMIDs: 9272157 (1997) and 10913957 (2000)). This variant has also been reported to have varying clinical consequence, with reduced CFTR function and protein expression at the cell surface (PMIDs: 23666117 (2013), 29805046 (2018), 34996830 (2022)). The frequency of this variant in the general population, 0.000032 (4/126666 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 28, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.;D;.

Eigen

Benign

0.051

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.34

N;.;.;.;N

MutationTaster

Benign

0.85

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

D;.;.;D;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

0.27

B;.;.;.;.

Vest4

0.84

MutPred

0.91

Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);.;Gain of MoRF binding (P = 0.0309);

MVP

1.0

MPC

0.0048

ClinPred

0.92

GERP RS

5.1

Varity_R

0.96

gMVP

0.97

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