rs121909020

Variant names:

• chr7-117611640-G-A
• rs121909020
• NM_000492.4:c.3199G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117611640-G-A
• chr7-117611640-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3_Moderate

The NM_000492.4(CFTR):​c.3199G>A​(p.Ala1067Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1067V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:2 U:5 O:1
• Conservation: PhyloP100: 9.94
• Publications: 40 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611641-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53683.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3199G>A	p.Ala1067Thr	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+4589C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3199G>A	p.Ala1067Thr	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250886 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461356 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726956

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111720

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000125 Hom.: 1

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ClinVar

Significance: drug response

Submissions summary: Pathogenic:2 Uncertain:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2

Jan 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1067T variant (also known as c.3199G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3199. The alanine at codon 1067 is replaced by threonine, an amino acid with similar properties. This variant was originally reported to be in trans with p.F508del in a child with cystic fibrosis (Férec C et al. Nat. Genet., 1992 Jun;1:188-91). Multiple studies demonstrated that this variant impairs CFTR maturation and function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). However, p.A1067T has never been observed in isolation and always co-occurred with p.F508del, and segregation analysis determined that the two variants are in cis and form a complex allele, p.[F508del;A1067T] (Culard JF et al. Hum. Genet., 1994 Apr;93:467-70; de Meeus A et al. Hum. Mutat., 1998;11:480; Claustres M et al. Hum Mutat, 2017 10;38:1297-1315; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jun 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 1067 of the CFTR protein (p.Ala1067Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with cystic fibrosis and pancreatic insufficiency and in an individual with congenital bilateral aplasia of vas deferens, both of whom also were found to have a p.Phe508del variant in CFTR. In at least one instance, this variant has been reported to occur on the same chromosome as p.Phe508del (PMID: 1284639, 10200050). ClinVar contains an entry for this variant (Variation ID: 7159). 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 (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 11242048, 23891399, 28003367). This variant disrupts the p.Phe508 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1284639, 10200050). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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:2

Jun 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3199G>A (p.Ala1067Thr) variant has been reported in the published literature in a 2 year-old individual with pancreatic insufficient cystic fibrosis (CF) or mild symptoms (PMID: 1284639 (1992) and CF Mutation Database (http://www.genet.sickkids.on.ca/)). This variant has been observed in additional cohorts with CF (PMIDs: 34782259 (2021), 7529319 (1994)) or congenital absence of the vas deferens (CBAVD) (PMIDs: 10923036 (2000), 9239681 (1996)). In multiple individuals with CBAVD, this variant occurred on the same chromosome as the c.1521_1523del (p.Phe508del or Delta F508) CF pathogenic variant (PMIDs: 28603918 (2017), 10200050 (1998), 7513294 (1994)). Experimental studies indicate the c.3199G>A (p.Ala1067Thr) variant has deleterious effects on CFTR function (PMIDs: 23891399 (2014), 11242048 (2001), 8702904 (1996), 8662892 (1996)). The frequency of this variant in the general population, 0.000004 (1/250886 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Apr 16, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:1

Mar 05, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 18, 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.3199G>A (p.Ala1067Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 4e-06 in 250886 control chromosomes. c.3199G>A has been reported in the literature in an individual affected with Cystic Fibrosis who had F508del in trans (Ferec_1992). In other patients with Cystic Fibrosis or CBAVD, the variant was found in cis with p.F508del (e.g. Culard_1994, de Meeus_1998, Claustres_2017, Raraigh_2022). These data do not allow any conclusion about variant significance. Publications report experimental evidence evaluating an impact on protein function (Cotten_1996, Seibert_1996, van Goor_2014), finding that the variant results in reduced mature CFTR protein and impaired channel function (VanGoor_2014, Seibert_1996b, Cotten_1996, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 28603918, 8702904, 7513294, 1284639, 34782259, 8662892, 23891399, 10200050, 38388235). ClinVar contains an entry for this variant (Variation ID: 7159). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

ivacaftor response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.97
MVP		1.0
MPC		0.017
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		0.0016	Neutral
Varity_R		0.83
gMVP		0.98
Mutation Taster		=4/96	disease causing

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: rs121909020; hg19: chr7-117251694;