NM_000492.4:c.1001G>A

Variant names:

• chr7-117540231-G-A
• rs397508137
• NM_000492.4:c.1001G>A
• CFTR p.Arg334Gln

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3PP5_Strong

The NM_000492.4(CFTR):c.1001G>A (p.Arg334Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000185 (AC=298) in the gnomAD database across 1,614,010 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000181. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.60). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV000696814: "At least two studies showed this variant results in approximately 20-30% chloride channel function compared to the WT protein (Han_2018, Raraigh_2018, Bihler_2024)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R334L: Pathogenic (ClinVar VariationId 53160, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R334= (synonymous): Likely_benign (ClinVar VariationId 4868842, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:5
• Conservation: PhyloP100: 7.60
• Publications: 10 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):

• congenital bilateral aplasia of vas deferens from CFTR mutation

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women's Health, ClinGen, Natera, 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000696814: "At least two studies showed this variant results in approximately 20-30% chloride channel function compared to the WT protein (Han_2018, Raraigh_2018, Bihler_2024)."; SCV001169725: Although this variant did not completely abolish CFTR function, it impaired CFTR function significantly (Gong X et al. Arch. Biochem. Biophys., 2004 Jun;426:78-82; Linsdell P. Biochim Biophys Acta, 2015 Jul;1848:1573-90; Han ST et al. JCI Insight, 2018 07;3: Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077).; SCV000603057: Functional studies have shown this variant to cause a disruption of anion interactions with the CFTR pore (Gong 2003, Linsdell 2015, Smith 2001, Zhou 2007), resulting in reduced chloride conductance (Gong 2004).; SCV004753069: This variant has been shown to weaken CFTR channel function and has been reported in patients with congenital bilateral absence of vas deferens (Li et al. 2012. PubMed ID: 22612315; Dayangac et al. PubMed ID: 15070876; Morea et al. 2005. PubMed ID: 16126774).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000181 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R334L: Pathogenic (ClinVar VariationId 53160, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R334= (synonymous): Likely_benign (ClinVar VariationId 4868842, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (16/20 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR NM_000492.4	MANE Select	c.1001G>A p.Arg334Gln	missense	Exon 8 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.1001G>Ap.Arg334Gln

Exon rankExon 8 of 27

missense

Prot: NP_000483.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR ENST00000003084.11	TSL:1MANE Select	c.1001G>A p.Arg334Gln	missense	Exon 8 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.1001G>A p.Arg334Gln	missense	Exon 8 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.1001G>A p.Arg334Gln	missense	Exon 8 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.1001G>Ap.Arg334Gln

Exon rankExon 8 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.1001G>Ap.Arg334Gln

Exon rankExon 8 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.1001G>Ap.Arg334Gln

Exon rankExon 8 of 26

missense

Prot: ENSP00000559265.1UniProt: A0ACI8SBR8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000921	AC:14	Hom:0	AN:152044	Cov:32
GnomAD2 exomes	AF: 0.000111	AC:28	Hom:	AN:251222	Cov:
GnomAD4 exome	AF: 0.000194	AC:284	Hom:0	AN:1461848	Cov:31
GnomAD4 genome	AF: 0.0000920	AC:14	Hom:0	AN:152162	Cov:32
TOPMed (Bravo)	AF: 0.000121	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000109	AC:12	Hom:0	AN:109944	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5176	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000671 *	1	1490	0.00 *	0	7190
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.000173	5	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000598	4	66888
SCHEMA(Schizophrenia)	0.000139	17	121948	0.000142	27	190722

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	2	-	Cystic fibrosis (8)
3	2	-	not provided (5)
3	1	-	CFTR-related disorder (4)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Benign	0.28
GPN-Star LLR	N/A	-6.7
GPN-Star score	N/A	6.6
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.37	D
Mutation Taster	N/A	9/91	disease causing (ClinVar)
MutationAssessor	Benign	1.1	L
PhyloP100	Pathogenic	7.6
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.33	N
REVEL	Pathogenic	0.69
Sift	Benign	0.18	T
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.25
VESM-3B	Benign	-5.2

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs397508137;

hg19: chr7-117180285;

COSMIC: COSV50078148;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar