rs148519623

chr7-117536598-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 3.89

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CFTR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=5}. Variant chr7-117536598-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.794T>G	p.Met265Arg	missense_variant	7/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.794T>G	p.Met265Arg	missense_variant	7/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32

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: 3 AN: 245598 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132826

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: 34 AN: 1455702 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 724204

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: 5 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

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.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 2020	The p.M265R variant (also known as c.794T>G and 926T>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 poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2023	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. Four of five 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 (gnomAD). c.794T>G has been reported in the literature as a compound heterozygous genotype with p.F508del in individuals affected with features resembling Non-Classic Cystic Fibrosis ranging from CBAVD (example, Dork_1997, Goossens_2000), pancreatic insufficiency and intermediate levels of sweat chloride (example, McCague_2019). As of now, there are 7 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 two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent plasma membrane expression as measured by a cell surface ELISA assay in BHK cells (Okiyoneda_2013) and reduced CFTR function as assessed by a short circuit current measurement assay (Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 12900515, 10913957, 17440499, 30888834, 23666117, 25735457, 29805046, 26708955, 26471113, 36207272). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:1

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. -
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 -

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 disorders 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

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;D;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.34	N;.;.;.;N
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.50	T
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	D
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

Other links and lift over

dbSNP: rs148519623; hg19: chr7-117176652;