rs368505753

Variant names:

• chr7-117509069-C-T
• rs368505753
• NM_000492.4:c.200C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.200C>T​(p.Pro67Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,612,926 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 Pathogenic,drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000074533: Experimental studies have shown that this missense change affects CFTR function (PMID:23891399, 23974870)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:25 O:1
• Conservation: PhyloP100: 6.12
• Publications: 106 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000074533: Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870).; SCV000696882: This variant has been shown to display a mean chloride conductance <10% compared to wildtype (Sosnay_2013, Kraus_2007).; SCV001984854: Experimental studies have shown that this missense change affects the chloride conduction function in vitro (PMID:23974870, 23891399).; SCV002720940: In vitro functional studies showed that while CFTR transcripts with this pathogenic mutation had similar mRNA levels compared to wildtype, the amount of processed mature protein was significantly decreased (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36).; SCV004562666: "In vitro/In vivo functional analyses demonstrate altered CFTR protein folding, reduced mature CTFR protein, and reduced chloride transport." PMID:33781744; SCV000888075: Functional studies have shown that this variant has a damaging effect on CFTR maturation and function (PMID: 23974870 (2013), 23891399 (2014), 27660821 (2016), 33781744 (2021)).; SCV004046297: "In-vitro functional studies showed that this alteration affects the channel function." PMID:23974870, 23891399
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 7-117509069-C-T is Pathogenic according to our data. Variant chr7-117509069-C-T is described in ClinVar as Pathogenic|drug_response. ClinVar VariationId is 53425.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.200C>T	p.Pro67Leu	missense	Exon 3 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.200C>T	p.Pro67Leu	missense	Exon 3 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.200C>T	p.Pro67Leu	missense	Exon 3 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.200C>T	p.Pro67Leu	missense	Exon 3 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 251004 AF XY: 0.0000442

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: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1460724 Hom.: 0 Cov.: 29 AF XY: 0.000114 AC XY: 83 AN XY: 726752

African (AFR) AF: 0.0000897 AC: 3 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111296

Other (OTH) AF: 0.000149 AC: 9 AN: 60356

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000692 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic; drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Cystic fibrosis (10)
7	-	-	not provided (7)
4	-	-	CFTR-related disorder (4)
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 (1)
1	-	-	Hereditary pancreatitis (1)
-	-	-	ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.017
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.93
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368505753; hg19: chr7-117149123;