chr7-117530974-C-G

Position:

chr7-117530974-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.349C>G(p.Arg117Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,613,576 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 3.82

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117530974-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 7-117530974-C-G is Pathogenic according to our data. Variant chr7-117530974-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117530974-C-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.349C>G	p.Arg117Gly	missense_variant	4/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.349C>G	p.Arg117Gly	missense_variant	4/27	1	NM_000492.4	ENSP00000003084.6		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:

0.0000199

AC:

AN:

250944

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135604

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:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461402

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000693

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

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:

0.00000534

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 117 of the CFTR protein (p.Arg117Gly). This variant is present in population databases (rs77834169, gnomAD 0.004%). This missense change has been observed in individuals with clinical symptoms of CFTR-related conditions (PMID: 11119745, 29805046, 29944384, 30888834). ClinVar contains an entry for this variant (Variation ID: 53762). 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 expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 7529962, 11788090, 15482777, 21520337, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 04, 2022	The p.R117G pathogenic mutation (also known as c.349C>G), located in coding exon 4 of the CFTR gene, results from a C to G substitution at nucleotide position 349. The arginine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. The mutation has been reported as a variant of varying clinical consequences (VVCC) (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 November 14, 2018). It has been described in the heterozygous state in a male with congenital bilateral absence of the vas deferens (CBAVD); a second CFTR alteration was not observed (Claustres M et al. Hum. Mutat., 2000;16:143-56; Daudin M et al. Fertil. Steril., 2000 Dec;74:1164-74). In addition, this mutation was observed in conjunction with p.N34S in the SPINK1 gene in an individual with idiopathic pancreatitis (Masson E et al. PLoS ONE. 2013; 8(8):e73522). In an in vitro study, the R117G protein had 35% of normal CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants at the same position and in the same region (Liu F et al. Cell, 2017 03;169:85-95.e8). Furthermore, there are also multiple pathogenic alterations at this same position, including p.R117H and p.R117C (Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on available evidence to date, this variant has not been reported as causative of classic CF; however, it may contribute to the development of a CFTR-related disorder and is thus classified as as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 17, 2019	Previously reported disease-causing CFTR variant associated with varying clinical consequences. See www.CFTR2.org for phenotype information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2023	Variant summary: CFTR c.349C>G (p.Arg117Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 2e-05 in 250944 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.349C>G has been reported in the literature in multiple compound heterozygous individuals affected with Cystic Fibrosis (Desai_2018, McCague_2019) as well as in individuals with pancreatitis (e.g., Masson_2013) and congenital bilateral absence of the vas deferens (e.g., Daudin_2000). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in approximately 35% overall function (compared to WT) (Raraigh_2018). Eight ClinVar submitters (evaluation after 2014) have cited the variant, with six submitters classifying the variant as pathogenic (n=3)/likely pathogenic (n=3), and two submitters classifying the variant as uncertain significance. Additionally, different missense variants affecting the same codon have been reported as pathogenic by our lab (p.R117C, p.R117H, p.R117L).Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2019	The CFTR c.349C>G; p.Arg117Gly variant (rs77834169) has been described in individuals with cystic fibrosis (CF) when found in trans to another CF-causing variant, but has also been described in association with other CFTR-related disorders such as congenital bilateral absence of vas deferens or pancreatitis in individuals that do not have CF (see link to CFTR2 database, Daudin 2000, Masson 2013). This variant is reported in ClinVar (Variation ID: 53762) and is found in the general population with an overall allele frequency of 0.002% (6/282344 alleles) in the Genome Aggregation Database. The arginine at residue 117 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.773). Due to this variant having a variable presentation in affected individuals, it is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://www.cftr2.org/ Daudin M et al. Congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. 2000;Fertil Steril. 74(6):1164-74. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. 2013;PLoS One. 8(8):e73522. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 26, 2024	The CFTR c.349C>G (p.Arg117Gly) variant has been reported as a variant of varying clinical consequences (VVCC) (PMID: 36409994 (2022) and CFTR2 (https://cftr2.org/)). This variant has been observed in individuals with clinical symptoms of CFTR-related conditions (PMIDs: 29944384 (2018)) and 30888834 (2019)) including individuals with pancreatitis (PMIDs: 18687795 (2008) and 23951356 (2013)) and congenital bilateral absence of the vas deferens (PMIDs: 11119745 (2000) and 10923036 (2000)). Experimental studies have indicated that the variant has reduced CFTR activity compared to the wild type CFTR, however the effect is still inconclusive (PMIDs: 29805046 (2018), 30888834 (2019), and 38388235 (2024)). In addition, other pathogenic variants have been reported at the same positions, including p.R117H and p.R117C (PMIDs: 19880712 (2009) and 23974870 (2013)). The frequency of this variant in the general population, 0.000039 (5/128904 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 53762). Based on the available information, this variant is classified as likely pathogenic. -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 18, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;D;.;.;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;L;.;.;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.9

D;N;.;.;N;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.96

MutPred

0.91

.;Loss of ubiquitination at K114 (P = 0.0709);Loss of ubiquitination at K114 (P = 0.0709);Loss of ubiquitination at K114 (P = 0.0709);Loss of ubiquitination at K114 (P = 0.0709);Loss of ubiquitination at K114 (P = 0.0709);

MVP

0.99

MPC

0.0098

ClinPred

0.89

GERP RS

5.7

Varity_R

0.79

gMVP

0.95

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