rs191456345

Positions:

chr7-117536576-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000492.4(CFTR):c.772A>G(p.Arg258Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,602,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:5

Conservation

PhyloP100: 3.33

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 Uncertain_significance. Variant got 5 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;

PP5

Variant 7-117536576-A-G is Pathogenic according to our data. Variant chr7-117536576-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54055.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=5, Pathogenic=6}. Variant chr7-117536576-A-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.772A>G	p.Arg258Gly	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.772A>G	p.Arg258Gly	missense_variant	7/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000182

AC:

AN:

235736

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

127228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000927

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:

0.0000951

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.0000931

AC:

135

AN:

1450194

Hom.:

Cov.:

AF XY:

0.0000791

AC XY:

AN XY:

720634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000776

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:

0.0000832

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000118

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 24, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 29, 2018	The CFTR c.772A>G (p.Arg258Gly) missense variant has been reported in four studies in which it is found in a total of seven affected individuals including in a compound heterozygous state in three individuals affected with congenital bilateral absence of vas deferens (CBAVD) (Mercier et al. 1995; Casals et al. 2000; Masvidal et al. 2009); in a compound heterozygous state in one individual affected with congenital unilateral absence of vas deferens (CUAVD) plus contralateral dysplasia of seminal vesicle (Masvidal et al. 2009); and in a heterozygous state in one individual affected with CBAVD (Grangeia et al. 2007), one individual affected with chronic pancreatitis and another with bronchiectasis (Masvidal et al. 2009). The individual with bronchiectasis also carried a known complex allele in cis (Masvidal et al. 2009). The p.Arg258Gly variant has not been reported in association with cystic fibrosis.The p.Arg258Gly variant was absent from 374 unaffected individuals and 250 cystic fibrosis patients (Mercier et al. 1995; Masvidal et al. 2009) but is reported at a frequency of 0.00167 in the Latino population of the Exome Aggregation Consortium. The variant is located in the second intracellular loop of the CFTR protein, a region known to highly conserved and contain other missense variants resulting in a CFTR-related disorders phenotype. Expression studies in HEK-293 and in CHO cells showed that the p.Arg258Gly variant resulted in incomplete glycosylation (less than 5% of wildtype levels) and was not transported to the cell surface (Seibert et al. 2007). Lack of surface expression resulted in loss of anion translocation capability of the CFTR protein (Seibert et al. 2007). Surface expression of the variant protein could be rescued by incubation of BHK cells stably transfected with the p.Arg258Gly variant with a quinazoline derivative, as determined by the iodide efflux assay (Loo et al. 2005). Based on the collective clinical and functional evidence, the p.Arg258Gly variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2023	The p.R258G variant (also known as c.772A>G), located in coding exon 7 of the CFTR gene, results from an A to G substitution at nucleotide position 772. The arginine at codon 258 is replaced by glycine, an amino acid with dissimilar properties. This alteration was first described in trans with p.F508del in a male with congenital bilateral absence of the vas deferens (CBAVD) (Mercier B et al. Am. J. Hum. Genet., 1995 Jan;56:272-7). Another study described this variant in five unrelated individuals with CFTR-related disorders; three individuals with CBAVD were compound heterozygotes with another CFTR alteration, while one individual with chronic pancreatitis carried only this alteration and one individual with bronchiectasis carried this alteration in cis with two other CFTR alterations (Masvidal L et al. Genet Test Mol Biomarkers, 2009 Dec;13:765-8). This alteration was also identified in a male with CBAVD in conjunction with p.S945L; however, the phase was not provided (Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). A functional study found this alteration inhibited the maturation and transportation of the CFTR protein to the cell surface (Seibert FS et al. Biochemistry, 1997 Sep;36:11966-74). The p.R258G variant 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 January 15, 2020). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 258 of the CFTR protein (p.Arg258Gly). This variant is present in population databases (rs191456345, gnomAD 0.08%). This missense change has been observed in individuals with CFTR-related conditions (PMID: 7529962, 10376575, 11466205, 19810821). ClinVar contains an entry for this variant (Variation ID: 54055). 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: 9305991, 16196493, 23104983). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2022	The CFTR c.772A>G; p.Arg258Gly variant (rs191456345) is reported in the literature in multiple individuals affected with congenital absence of the vas deferens or other CFTR-related disorders, including several individuals who carried a second pathogenic CFTR variant (Casals 2000, Chillon 1995, Masvidal 2009, Mercier 1995). This variant is also reported in the CFTR2 database, and in ClinVar (Variation ID: 54055). This variant is found in the general population with an overall allele frequency of 0.017% (46/267144 alleles) in the Genome Aggregation Database. The arginine at codon 258 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.896). Functional analyses of the variant protein show reduced cell surface expression and decreased channel function (Seibert 1997). Based on available information, this variant is considered to be mildly pathogenic, but is not predicted to cause classic cystic fibrosis. References: Link to CFTR2 database: https://cftr2.org/ Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. PMID: 10875853. Chillon M et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475-80. PMID: 7739684. Masvidal L et al. The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders. Genet Test Mol Biomarkers. 2009 Dec;13(6):765-8. PMID: 19810821. Mercier B et al. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995 Jan;56(1):272-7. PMID: 7529962. Seibert FS et al. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Biochemistry. 1997 Sep 30;36(39):11966-74. PMID: 9305991. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2017	- -

CFTR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 18, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 29, 2024	The CFTR c.772A>G variant is predicted to result in the amino acid substitution p.Arg258Gly. This variant has been reported in the compound heterozygous state with known pathogenic variants in patients with cystic fibrosis related disorders including congenital bilateral absence of vas deferens, chronic pancreatitis and bronchiectasis (Chillón et al. 1995. PubMed ID: 7739684; Mercier et al. 1995. PubMed ID: 7529962; Mak et al. 1999. PubMed ID: 10376575; Larriba et al. 2001. PubMed ID: 11466205; Masividal et al. 2009. PubMed ID: 19810821). Expression studies in COS-1 and HEK293 cells showed impaired CFTR surface expression (Seibert et al. 1997. PubMed ID: 9305991). This variant is reported in 0.090% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2024	Variant summary: CFTR c.772A>G (p.Arg258Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPRIPR011527) 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 0.00019 in 236970 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (0.00019 vs 0.013), allowing no conclusion about variant significance. c.772A>G has been reported in CBAVD patients in compound heterozygosity with disease causing CFTR alleles including DeltaF508, Ser945Leu, and Tyr1092X, indicating pathogenicity for CBAVD (examples: Chillon_1995, Masvidal_2009). Additionally, a functional study on this mutation revealed that the Arg258Gly variant disrupts biosynthesis of the protein; inhibits maturation and transport of the CFTR protein to the cell surface, and reduces the anion translocation capability of CFTR (Seibert et al., 1997) further supporting a deleterious impact. However, one recent functional study reported the variant to have wild-type levels of CFTR-dependent Cl- transport (Pranke_2017). The following publications have been ascertained in the context of this evaluation (PMID: 15097853, 7739684, 9239681, 17413420, 23104983, 25033378, 22483971, 16196493, 10376575, 19810821, 7529962, 34196078, 28785019, 25735457, 36409994, 9305991, 34442373, 23687349, 28830496, 19812525). ClinVar contains an entry for this variant (Variation ID: 54055). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 23, 2018	The p.Arg258Gly variant in CFTR has been reported in 7 individuals with CFTR-rel ated disorders, including 4 with congenital absence of the vas deferens (CAVD; M ercier 1995, Casals 2000, Grangeia 2007, Masvidal 2009). In three individuals, a variant affecting the second copy of CFTR was not identified. In the other 4 in dividuals, all of whom with CAVD, the p.Arg258Gly was identified in the compound heterozygote state with other CFTR variants, of which at least three were patho genic. The p.Arg258Gly variant has also been reported by other clinical laborato ries in ClinVar (Variation ID: 54055). In vitro functional studies provide some evidence that the p.Arg258Gly variant may impact protein function due to imprope r shuttling to the plasma membrane (Seibert 1997, Loo 2005). Additionally, this variant has been identified in 27/33360 Latino chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establis h its clinical significance, the p.Arg258Gly variant is likely pathogenic for CF TR-related disorders, particularly CVAD, in an autosomal recessive manner based upon presence in multiple affected individuals and functional evidence . ACMG/AM P criteria applied: PM3_VeryStrong, PS3_Moderate. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 19, 2023

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.0

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.6

D;.;.;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

0.89

P;.;.;.;.

Vest4

0.97

MVP

0.99

MPC

0.015

ClinPred

0.34

GERP RS

5.1

Varity_R

0.97

gMVP

0.99

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