7-117610568-C-T

Variant names:

• chr7-117610568-C-T
• rs193922516
• NM_000492.4:c.3038C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.3038C>T​(p.Pro1013Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,332 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. P1013H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:7 O:1
• Conservation: PhyloP100: 7.52

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]

ENSG00000083622 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117610568-C-A is described in Lovd as [Likely_pathogenic].
• 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, congenital bilateral absence of vas deferens, cystic fibrosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-117610568-C-T is Pathogenic according to our data. Variant chr7-117610568-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53634.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3038C>T	p.Pro1013Leu	missense_variant	Exon 19 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3038C>T	p.Pro1013Leu	missense_variant	Exon 19 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152012 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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251138 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461204 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726912

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33446

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44670

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26118

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39666

Gnomad4 SAS exome AF: 0.000243 AC: 21 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53396

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1111542

Gnomad4 Remaining exome AF: 0.0000828 AC: 5 AN: 60354

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207814 AN: 0.000207814

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000474 AC: 0.000473934 AN: 0.000473934

Alfa AF: 0.00000833 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:4 Other:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1013 of the CFTR protein (p.Pro1013Leu). This variant is present in population databases (rs193922516, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9521595, 17594398, 23613805, 34860163). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53634). 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: 11278813). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 12, 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. -

Nov 06, 2019

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria Codes: PP3 PM3 PM1_Supp PM2 -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 30, 2020

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 12, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1013L variant (also known as c.3038C>T), located in coding exon 19 of the CFTR gene, results from a C to T substitution at nucleotide position 3038. The proline at codon 1013 is replaced by leucine, an amino acid with similar properties. This variant was initially reported in a Turkish individual with cystic fibrosis (CF), elevated sweat chloride levels, and an intronic variant confirmed in trans (Onay T et al. Hum. Genet., 1998 Feb;102:224-30). It has also been reported in two siblings with a diagnosis of CF; both siblings were also heterozygous for p.F508del (phase not provided) (Schippa S et al. PLoS ONE, 2013 Apr;8:e61176). In a newborn with an elevated immunoreactive trypsinogen and normal sweat chloride levels, this variant was identified in conjunction with p.F508del; at four years, this individual was asymptomatic with normal sweat chloride levels, normal height and weight, and negative bacterial cultures (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). 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 available evidence to date, the clinical significance of this alteration remains unclear. -

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

May 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 04, 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.3038C>T (p.Pro1013Leu) 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 3.2e-05 in 251138 control chromosomes. c.3038C>T has been reported in the literature in the compound heterozygous state or an unknown state in multiple individuals affected with clinical features of Cystic Fibrosis and/or testing positive for CF upon NBS (example, Onay_1998, Kilinc_2002, Elahi_2006, Narzi_2007, Schippa_2013, Lucarelli_2015, Castaldo_2020, Bozdogan_2021, Erdoan_2021, Saferali_2022, Ahting_2024, Nunziato_2024, Yldz_2024), including at least 1 family where 2 siblings carried a pathogenic variant in trans segregating with disease. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 30.71% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 37867076, 38388235, 12007216, 33572515, 32784480, 11504857, 16436643, 34860163, 11278813, 34426522, 12439892, 25880441, 25910067, 17594398, 37923102, 9521595, 25735457, 34996830, 23613805, 26437683, 39031495). ClinVar contains an entry for this variant (Variation ID: 53634). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CFTR-related disorder Uncertain:1

Nov 22, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.0	D;.;.;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.94
MutPred		0.91		Gain of helix (P = 0.132);.;.;.;.;
MVP		1.0
MPC		0.016
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.81
gMVP		0.98
Mutation Taster		=1/99	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922516; hg19: chr7-117250622;