7-117592419-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000492.4(CFTR):c.2252G>T(p.Arg751Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,460,366 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. R751C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7
• Conservation: PhyloP100: 4.33

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 7-117592419-G-T is Pathogenic according to our data. Variant chr7-117592419-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235245.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=7}. Variant chr7-117592419-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2252G>T	p.Arg751Leu	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2252G>T	p.Arg751Leu	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249372 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134796

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460366 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 02, 2023	The p.R751L variant (also known as c.2252G>T), located in coding exon 14 of the CFTR gene, results from a G to T substitution at nucleotide position 2252. The arginine at codon 751 is replaced by leucine, an amino acid with dissimilar properties. This alteration, along with the deltaF508 pathogenic mutation, was described in an individual who presented with pancreatic sufficient cystic fibrosis. However, information if this alteration was in cis or trans with deltaF508 was not available (Goubau C et al. Thorax 2009; 64:683-91). Functional studies demonstrated that this variant is functional and biochemical responses were similar to the wildtype CFTR protein level (Haq IJ et al. Am J Physiol Lung Cell Mol Physiol, 2021 Feb;320:L288-L300). This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 751 of the CFTR protein (p.Arg751Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 19318346, 33296276). ClinVar contains an entry for this variant (Variation ID: 235245). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 33296276). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 26, 2019	The CFTR c.2252G>T; p.Arg751Leu variant (rs397508357) is reported in the literature in an individual affected with pancreatic-sufficient cystic fibrosis that also carried the pathogenic p.Phe508del variant (Goubau 2009). In testing performed at ARUP, the p.Arg751Leu variant has also been seen in a newborn with elevated sweat chloride that also carried a nonsense variant in CFTR. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 751 is moderately conserved and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Arg751Leu variant is uncertain at this time. References: Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2024	Variant summary: CFTR c.2252G>T (p.Arg751Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 249372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2252G>T has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as compound heterozygous with pathogenic variants (e.g. Goubau_2009, Coffey_2017, Haq_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Haq_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19318346, 27837951, 33296276). ClinVar contains an entry for this variant (Variation ID: 235245). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 30, 2015

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2023

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;.
Eigen	Benign	0.077
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;.;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D;.;D;.
Sift4G	Uncertain	0.0020	D;.;D;.
Polyphen		0.28	B;.;.;.
Vest4		0.79
MVP		0.99
MPC		0.0050
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.52

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: rs397508357; hg19: chr7-117232473;