chr7-117535269-G-A

Variant names:

• chr7-117535269-G-A
• rs138338446
• NM_000492.4:c.601G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_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 (★★★). Synonymous variant affecting the same amino acid position (i.e. V201V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:15
• Conservation: PhyloP100: 2.81
• Publications: 51 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 1 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15366998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.601G>A	p.Val201Met	missense_variant	Exon 6 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.601G>A	p.Val201Met	missense_variant	Exon 6 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152068 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251432 AF XY: 0.000243

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 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.: 1 Cov.: 32 AF XY: 0.000138 AC XY: 100 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111990

Other (OTH) AF: 0.000546 AC: 33 AN: 60394

GnomAD4 genome AF: 0.000467 AC: 71 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74408

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.00314 AC: 48 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67994

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000278 Hom.: 1

Bravo AF: 0.00124

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:15

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:7

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

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 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; internal data). 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). 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: 21708286, 27738188). For these reasons, this variant has been classified as Pathogenic. -

Jun 11, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information. -

Mar 20, 2025

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant NM_000492.4(CFTR):c.601G>A (p.Val201Met) has GnomAD 4.1 frequency of 0.0001685 with 1 homozygote. Reported as likely pathogenic in PMID 29805046 -

Mar 31, 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. -

Mar 26, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 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.601G>A (p.Val201Met) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00023 in 251432 control chromosomes in the gnomAD database, including 1 homozygote. 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 observed in the presumed or confirmed compound heterozygous state as an isolated variant allele (i.e. not on a haplotype) in multiple individuals affected with primarily Non-Classic Cystic Fibrosis (CBAVD, Cystic Fibrosis Screening Positive Inconclusive Diagnosis [CFSPID], sweat test-positive newborn screening with presumptive diagnosis of CF, CF-related conditions) (example, Boudaya_2012, Steiner_2011, Mota_2018, Girardet_2015, Thimmesch_2024, Castaldo_2020, Hu_2024, CFTR-France Database, internal data). These data indicate that the variant in isolation is very likely to be associated with primarily mild-spectrum CFTR-related disease. Further, the V201M component of the common pathogenic haplotype p.[R74W;V201M;D1270N] is considered by our laboratory to be the primary variation responsible for clinical presentation, as the other 2 variants R74W and D1270N are likely to be in cis and approach or exceed (0.01253-0.01388 with 3-10 homozygotes across gnomAD v2/v4) the maximum expected pathogenic allele frequency for CFTR-related conditions (0.013), yet lack robust clinical data when alone (ClinVar). In at least 1 study, p.[R74W;D1270N] in the absence of V201M was observed in trans with a well-established pathogenic variant in an unaffected female individual with multiple negative sweat test results (Claustres_2004), suggesting p.[R74W;D1270N] is unlikely to cause severe non-CBAVD CFTR-related disease in the absence of V201M. At least one publication reports experimental evidence evaluating an impact on protein function for isolated V201M in vitro. The most pronounced isolated variant effect resulted in approximately 23.43% of normal chloride channel conductance relative to wild type, as compared to R74W (37.4%) or D1270N (50.95%) in isolation or 5.97% for the p.[R74W;V201M;D1270N] haplotype (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 10794365, 22148899, 36796836, 32357917, 14998948, 20021716, 38695616, 36832409, 29805046, 37431359, 30232781, 36409994, 21520337, 27738188, 20217271, 15905293, 36834620, 38388235, 39570414, 38388235, 32784480, 39402445, 24762087, 15287992). ClinVar contains an entry for this variant (Variation ID: 54022). Based on the evidence outlined above, the variant was classified as pathogenic, whether on the haplotype or in isolation. -

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sweat chloride; however, a second alteration was not identified (Bernardino AL et al. Genet Test, 2000;4:69-74). In addition, this variant has been detected in conjunction with a pathogenic CFTR variant in a child with elevated sweat chloride levels and a man with congenital absence of the vas deferens (CBAVD) (Mota LR et al. Mol Biol Rep, 2018 Dec;45:2045-2051; Steiner B et al. Hum Mutat, 2011 Aug;32:912-20). This variant often occurs as part of a complex allele, p.[R74W;R1070W;D1270N]. The complex allele has been identified in the homozygous state and in trans with a pathogenic CFTR mutation in multiple individuals with cystic fibrosis and CFTR-related disorders (Claustres M et al. BMC Med Genet, 2004 Aug;5:19; Steiner B et al. Hum Mutat, 2011 Aug;32:912-20; Lucarelli M et al. Mol Med, 2015 Apr;21:257-75; Terlizzi V et al. J Med Genet, 2017 Apr;54:224-235). 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 studies demonstrated that this variant on its own reduces CFTR activity, but the presence of the other variants (p.R74W and p.D1270N) in cis results in further reduction (Raraigh KS et al. Am J Hum Genet, 2018 Jun;102:1062-1077; Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). 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 the available evidence, the clinical significance of this variant remains unclear. -

Mar 03, 2017

CFTR2

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: research

- -

not provided Uncertain:6

Oct 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (v2.1.1). 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. -

Feb 07, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 25, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 23, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Uncertain:2

Mar 26, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.2	L;.;.;.;L
PhyloP100		2.8
PrimateAI	Uncertain	0.63	T
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	T
GERP RS		4.6
Varity_R		0.40
gMVP		0.84
Mutation Taster		=75/25	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs138338446; hg19: chr7-117175323;