rs148519623

Variant names:

• chr7-117536598-T-G
• rs148519623
• NM_000492.4:c.794T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP2 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:8 U:3
• Conservation: PhyloP100: 3.89
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• 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 VariationId is 54058.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.794T>G	p.Met265Arg	missense_variant	Exon 7 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.794T>G	p.Met265Arg	missense_variant	Exon 7 of 27	1	NM_000492.4	ENSP00000003084.6

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

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245598 AF XY: 0.0000226

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1108514

Other (OTH) AF: 0.0000498 AC: 3 AN: 60188

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:2

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 04, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

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:2

Apr 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 pathogenic for varying clinical consequences. References: CFTR2 database: https://cftr2.org/ SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997; 100(3-4):365-77. PMID: 9272157 Goossens V et al. Clinical application of preimplantation genetic diagnosis for cystic fibrosis. Prenat Diagn. 2000 Jul;20(7):571-81. PMID: 10913957 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. PMID: 29805046 -

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:1

Aug 28, 2018

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Nov 27, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 24, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
PhyloP100		3.9
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
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs148519623; hg19: chr7-117176652;