rs138338446

Positions:

chr7-117535269-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.601G>A(p.Val201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:17

Conservation

PhyloP100: 2.81

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 2 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.15366998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.601G>A	p.Val201Met	missense_variant	6/27	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.601G>A	p.Val201Met	missense_variant	6/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00315

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:

0.000221

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251432

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000137

AC:

201

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000467

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:8

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 2023	The p.V201M variant (also known as c.601G>A), located in coding exon 6 of the CFTR gene, results from a G to A substitution at nucleotide position 601. The valine at codon 201 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in isolation in a child with mild pulmonary disease, pancreatic sufficiency, and elevated; however, a second alteration was not identified (Bernardino AL et al. Genet. Test., 2000;4:69-74). In a child with a positive newborn screen, elevated sweat chloride levels, and steatorrhea, this variant was identified in conjunction with p.G542*; however, phase was not provided (Mota LR et al. Mol. Biol. Rep., 2018 Sep;45(6):2045–51). It was also identified in isolation in men with congenital absence of the vas deferens (CBAVD), including in one male who was also heterozygous for p.F508del; however, the phase was not confirmed (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6; Wu CC et al. Hum. Reprod., 2005 Sep;20:2470-5;Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In addition, this variant has also been observed as part of the complex allele p.[R74W;V201M;D1270N] (de Prada Merino A et al. J. Cyst. Fibros., 2010 Dec;9:447-9). The complex allele has been identified in the homozygous state and in trans with a pathogenic mutation in CFTR in individuals with CBAVD (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In one report, two young boys carried the complex allele in trans with p.F508del and were asymptomatic; however, CBAVD was not ruled out (Brugnon F et al. Fertil. Steril., 2008 Nov;90:2004.e23-6). Functional analysis of this variant in CFBE cells demonstrated 48% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). 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 available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 11, 2020	CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 201 of the CFTR protein (p.Val201Met). This variant is present in population databases (rs138338446, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cystic fibrosis or congenital bilateral absence of the vas deferens (PMID: 15287992, 16963320, 19897426, 21520337, 21658649, 25910067, 27738188, 30232781; Invitae). 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: 54022). 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: 21708286, 27738188). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 31, 2017	- -
Uncertain significance, reviewed by expert panel	research	CFTR2	Mar 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 20, 2022	The CFTR c.601G>A; p.Val201Met variant (rs138338446) has been identified without an additional pathogenic variant in an individual with a clinical diagnosis of cystic fibrosis (CF), individuals with congenital bilateral absence of the vas deferens (CBAVD) (Bernardino 2000, Gallati 2009, Luo 2021, Steiner 2011, Wu 2005), and in one individual with CBAVD who also carried a severe pathogenic variant (Steiner 2011). However, this variant is most often identified in individuals with atypical CF as part of a complex variant on the same allele as other variants (Behar 2017, Brugnon 2008, Claustres 2004, Masson 2013, Steiner 2011, Terlizzi 2017). This variant is reported as an uncertain variant in ClinVar (Variation ID: 54022), and is found in the general population with an overall allele frequency of 0.02% (61/282812 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at this position is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.676). Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. PMID: 28546993. Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. PMID: 10794365. Brugnon F et al. Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. Fertil Steril. 2008 Nov;90(5):2004.e23-6. PMID: 18703181. Claustres M et al. Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations? BMC Med Genet. 2004 Aug 2;5:19. PMID: 15287992. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. PMID: 20021716. Luo S et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. PMID: 21520337. Terlizzi V et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet. 2017 Apr;54(4):224-235. PMID: 27738188. Wu CC et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005 Sep;20(9):2470-5. PMID: 15905293. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2016	The V201M variant in the CFTR gene has been reported previously as heterozygous in one child diagnosed with CF; no other variants in the CFTR gene were identified (Bernardino et al., 2000). The V201M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V201M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Pathogenic missense variants in nearby residues (H199Y, P205S) have been reported in the Human Gene Mutation Database in association with CF (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V201M as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 25, 2023	The CFTR c.601G>A (p.Val201Met) variant (also known as V201M) has been reported in the published literature in individuals affected with CF (PMID: 32819855 (2020)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 15905293 (2005), 22148899 (2012), 32777524 (2021)), in a child with a diagnosis of CF without a second mutation (PMID: 10794365 (2000)), and in a newborn carrying a pathogenic variant with normal sweat chloride but an elevated immunoreactive trypsin (IRT) (PMID: 30232781 (2018)). It was also identified in a cohort of infertile individuals (PMID: 32357917 (2020)). In addition, an experimental study indicated the variant has reduced CFTR activity, however with an inconclusive effect (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.0006208 (22/35436 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	PM2 -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 26, 2021	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 29, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 25, 2024

Variant summary: CFTR c.601G>A (p.Val201Met) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 0.00023 in 253560 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 (0.00023 vs 0.013), allowing no conclusion about variant significance. c.601G>A has been widely reported in the literature in sequencing studies among individuals affected with Non-classic Cystic Fibrosis, mainly CBAVD and mild CF phenotypes such as increased immunoreactive trypsin (IRT) and intermediate sweat chloride levels in settings of neonatal screening (example Bernarrdino_2000, Danziger_2004, Wu_2005, Gallati_2009, Tropel_2010, Steiner_2011, Boudaya_2012, Ribero Mota_2018, Chamayou_2020, Burgel_2023, Raymond_2023, Kay_2024). These data do not allow unequivocal conclusions about variant significance in isolation although the complex allele comprising this variant in cis with c.220C>T (p.Arg74Trp) and c.3808G>A (p.Asp1270Asn) is considered a common disease causing variant combination. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 48% of normal activity in an assay measuring CFTR Function by short-circuit chloride current measurements (Raraigh_2018). The authors report a CFTR2 database classification of this variant in isolation as "indeterminate". The following publications have been ascertained in the context of this evaluation (PMID: 10794365, 22148899, 36796836, 32357917, 14998948, 20021716, 38695616, 36832409, 29805046, 37431359, 30233781, 21520337, 27738188, 20217271, 15905293, 36834620). ClinVar contains an entry for this variant (Variation ID: 54022). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.2

L;.;.;.;L

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.96

N;.;.;N;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0050

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.94

P;.;.;.;.

Vest4

0.76

MVP

1.0

MPC

0.011

ClinPred

0.088

GERP RS

4.6

Varity_R

0.40

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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