rs193922501

chr7-117480108-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000492.4(CFTR):c.14C>T(p.Pro5Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,770 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:1
• Conservation: PhyloP100: 3.85

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 32 pathogenic changes around while only 4 benign (89%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117480108-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2873814.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 7-117480108-C-T is Pathogenic according to our data. Variant chr7-117480108-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35824.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Pathogenic=6, Uncertain_significance=1}. Variant chr7-117480108-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.14C>T	p.Pro5Leu	missense_variant	1/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.14C>T	p.Pro5Leu	missense_variant	1/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152052 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251160 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135748

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2024	The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 22, 2018). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). 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 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 13, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes (gnomAD and publication data). c.14C>T has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). Nine ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=1), likely pathogenic (n=4) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CFTR: PM3:Very Strong, PM2, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2020	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Aug 04, 2020

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.3	D;.;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.69
MutPred		0.73		Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);
MVP		0.99
MPC		0.011
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.86
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922501; hg19: chr7-117120162;