rs191456345

Variant names:

• chr7-117536576-A-G
• rs191456345
• NM_000492.4:c.772A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:5
• Conservation: PhyloP100: 3.33
• Publications: 24 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000492.4
• 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.
• 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 VariationId is 54055.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.772A>G	p.Arg258Gly	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.772A>G	p.Arg258Gly	missense_variant	Exon 7 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152218 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000182 AC: 43 AN: 235736 AF XY: 0.000126

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 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.: 0 Cov.: 31 AF XY: 0.0000791 AC XY: 57 AN XY: 720634

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.000776 AC: 34 AN: 43822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000832 AC: 92 AN: 1105524

Other (OTH) AF: 0.000150 AC: 9 AN: 59986

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000805 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 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. -

Apr 24, 2018

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. -

Nov 05, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). In multiple assays testing CFTR function, this variant showed functionally abnormal results (Seibert FS et al. Biochemistry, 1997 Sep;36:11966-74; Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). 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. -

Jan 29, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2 Uncertain:2

Jun 28, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 02, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:2

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jan 18, 2021

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2

Oct 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 29, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 F508del, Ser945Leu, and Tyr1092X, indicating pathogenicity for CBAVD (examples: Chillon_1995, Masvidal_2009). These data indicate that the variant is likely to be associated with disease. Additionally, functional studies have shown that the Arg258Gly variant disrupts biosynthesis of the protein, inhibits maturation and transport of the CFTR protein to the cell surface, and results in approximately 7% of normal chloride channel conductance relative to wild type (Seibert_1997, Bihler_2024). 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, 38388235). ClinVar contains an entry for this variant (Variation ID: 54055). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Sep 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 22, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;M
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
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	T
GERP RS		5.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=3/97	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: rs191456345; hg19: chr7-117176630;