rs373885282

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting

The NM_000492.4(CFTR):c.2758G>A(p.Val920Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,920 control chromosomes in the GnomAD database, including 2 homozygotes. 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. V920L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13O:1

Conservation

PhyloP100: 9.76

Publications

10 publications found

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 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)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 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.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2758G>A	p.Val920Met	missense_variant	Exon 17 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.2758G>A	p.Val920Met	missense_variant	Exon 17 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251402

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461766

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.000134

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000614

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1111932

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.000524

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:5Other:1

Nov 13, 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. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V920M variant (also known as c.2758G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2758. The valine at codon 920 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in multiple individuals with CFTR-related disorders, including recurrent pancreatitis, congenital bilateral absence of the vas deferens, and disseminated bronchiectasis; however, complete genotype information was not provided (Bernardino AL et al. JOP, 2003 Sep;4:169-77; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). 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 available evidence, the clinical significance of this alteration remains unclear. -

Oct 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 920 of the CFTR protein (p.Val920Met). This variant is present in population databases (rs373885282, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and idiopathic pancreatitis (PMID: 10923036, 14526128, 23951356). ClinVar contains an entry for this variant (Variation ID: 53561). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:5

Sep 28, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.2758G>A; p.Val920Met variant (rs373885282) is reported in the literature in the compound heterozygous state with a second pathogenic or pathogenic-mild variant in individuals affected with cystic fibrosis or CFTR-related disorders (see link to cystic fibrosis mutation database, Claustres 2000, Cohn 2005, Trujillano 2013). However, this variant is also reported in individuals affected with CFTR-related disorders in the heterozygous state without a second pathogenic variant (Amato 2012, Bernardino 2003, Rene 2011), or with other variants that potentially explain the phenotype (Groman 2002, Masson 2013). This variant is reported in ClinVar (Variation ID: 53561), and is found in the general population with an overall allele frequency of 0.013% (36/282810 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 920 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.792). Due to conflicting information, the clinical significance of the p.Val920Met variant is uncertain at this time. References: Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=398 Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. PMID: 22020151. Bernardino AL et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003 Sep;4(5):169-77. PMID: 14526128. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. PMID: 16134171. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002 Aug 8;347(6):401-7. PMID: 12167682. 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. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011 Jan;19(1):36-42. PMID: 20717170. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62. PMID: 23687349. -

May 15, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a CFTR variant in cis and an additional CF-causing variant in trans in an individual with meconium ileus, pancreatic insufficiency, nasal polyposis, pulmonary symptoms, and a positive sweat chloride test (PMID: 28603918); Observed both with and without additional CFTR variants in individuals with non classic cystic fibrosis, congenital absence of the vas deferens, pancreatitis, or bronchiectasis (PMID: 16134171, 22020151, 14526128, 28603918, 12167682); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15241793, 25087612, 9881185, 14526128, 20717170, 16134171, 20021716, 22020151, 21184098, 26436105, 20059485, 23951356, 12167682, 10923036, 33083013, 34996830, 35313924, 31655510, 38590877, 38388235, 28603918) -

Feb 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.2758G>A (p.Val920Met) variant has been reported in the published literature in individuals affected with cystic fibrosis (CF) (PMIDs: 36409994 (2022), 35313924 (2022), 12167682 (2002), 10923036 (2000)) and CFTR-related disorders (PMIDs: 23951356 (2013), 23687349 (2013), 22020151 (2012), 16134171 (2005), 14526128 (2003), 10923036 (2000)), however, genotype/phenotype data are limited and no definitive associations can be made at this time. It was also seen with two other deleterious variants in an individual affected with pancreatic-insufficient CF, suggesting this variant may not have been the cause of disease (PMID: 9881185 (1998)). This variant was also identified in reportedly healthy individuals (PMIDs: 21520337 (2011), 15241793 (2004)). The frequency of this variant in the general population, 0.00065 (20/30616 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Jan 28, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CFTR c.2758G>A (p.Val920Met) results in a 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 0.00014 in 252114 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.2758G>A has been reported in the literature in compound heterozygosity with p.F508del in individuals affected with Non-Classic Cystic Fibrosis or congenital absence of the vas deferens (Claustres_2000), with p.F508del and the 5T/13TG allele in an individual with Non-Classic Cystic Fibrosis (Groman_2002), and with 5T/13TG in an individual with a CFTR-related disorder (Trujillano_2013, Trujillano_2015). It has also been reported in individuals with chronic pancreatitis (Cohn_2005, Masson_2013), hyperechogenic fetal bowel (Rene_2011, deBecdelievre_2011), and in the heterozygous state without a second pathogenic variant specified in individuals with CFTR-related disorders (e.g. Amato_2012, Salinas_2023) as well as a healthy control individual (Steiner_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 37% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 22020151, 33083013, 10923036, 16134171, 12167682, 23951356, 20717170, 36409994, 21520337, 23687349, 26436105, 21184098, 38388235). ClinVar contains an entry for this variant (Variation ID: 53561). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CFTR-related disorder

Uncertain:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.2758G>A variant is predicted to result in the amino acid substitution p.Val920Met. This variant was observed in the compound heterozygous state with p.F508del in a patient with congenital absence of the vas deferens and another patient with non-classic CF (Claustres et al. 2000. PubMed ID: 10923036). The c.2758G>A (p.Val920Met) variant has also been reported alongside a 5T/13TG allele (phase not specified) in a patient with a CFTR-related disorder (Trujillano et al. 2013. PubMed ID: 23687349 and Trujillano et al. 2015. PubMed ID: 26436105), in trans with a variant of uncertain significance in a patient with chronic pancreatitis (Cohn et al. 2005. PubMed ID: 16134171), and in affected individuals with other variants that potentially explain the phenotype (Groman et al. 2002. PubMed ID: 12167682; Masson et al. 2013. PubMed ID: 23951356). This variant is also reported in the heterozygous state without a second pathogenic variant in patients affected with CFTR-related disorders (Amato et al. 2012. PubMed ID: 22020151; René et al. 2011. PubMed ID: 20717170; de Becdelièvre et al. 2011. PubMed ID: 21184098) but was seen in the heterozygous state in a healthy control individual (Steiner et al. 2011. PubMed ID: 21520337). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

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

0.60

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.;.;T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.73

N;.;.;N;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0060

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.84

MVP

1.0

MPC

0.0097

ClinPred

0.25

GERP RS

5.8

Varity_R

0.76

gMVP

0.86

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over