chr7-117590436-A-T

Variant names:

• chr7-117590436-A-T
• rs397508297
• NM_000492.4:c.1763A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.1763A>T​(p.Glu588Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,658 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 8.64

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 domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 7-117590436-A-T is Pathogenic according to our data. Variant chr7-117590436-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53375.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, not_provided=1}. Variant chr7-117590436-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1763A>T	p.Glu588Val	missense_variant	Exon 13 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1763A>T	p.Glu588Val	missense_variant	Exon 13 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448658 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720526

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: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:1 Other:1

Jan 29, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. -

Oct 30, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1763A>T (p.Glu588Val) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249708 control chromosomes (gnomAD and publication data). c.1763A>T has been reported in the literature in individuals affected with Cystic Fibrosis (Schrijver_2005, Storm_2007, Trujillano_2013). These data indicate that the variant is likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and the variant effect results in 10%-<30% of normal activity (Raraigh_2018). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E588V variant (also known as c.1763A>T), located in coding exon 13 of the CFTR gene, results from an A to T substitution at nucleotide position 1763. The glutamic acid at codon 588 is replaced by valine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variants in individuals, but clinical details were limited (Storm K, et al. J. Cyst. Fibros. 2007 Nov; 6(6):371-5; Schrijver I, et al. J Mol Diagn. 2005 May; 7(2):289-9; Trujillano et al J Med Genet. 2013;50(7):455-462). Functional studies suggest decreased activity; however, additional evidence is needed to confirm this finding (Raraigh KS et al. Am J Hum Genet, 2018 Jun;102:1062-1077; Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). 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. -

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 588 of the CFTR protein (p.Glu588Val). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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. ClinVar contains an entry for this variant (Variation ID: 53375). This missense change has been observed in individuals with clinical features of cystic fibrosis (PMID: 15858154, 17481968, 23687349, 28830496, 30888834; Invitae). This variant is not present in population databases (gnomAD no frequency). -

CFTR-related disorder Pathogenic:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.1763A>T variant is predicted to result in the amino acid substitution p.Glu588Val. This variant has been reported in multiple individuals with cystic fibrosis (see for example, Schrijver et al. 2005. PubMed ID: 15858154; Storm et al. 2007. PubMed ID: 17481968; De Wachter et al. 2017. PubMed ID: 28830496). An in vitro experimental study suggests this variant decrease protein function to 27.5% of wildtype-CFTR (Raraigh et al. 2018. PubMed ID: 29805046). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.0040	D;.;D;.
Polyphen		0.99	D;.;.;.
Vest4		0.92
MutPred		0.87		Loss of ubiquitination at K593 (P = 0.059);.;.;.;
MVP		0.98
MPC		0.0075
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs397508297; hg19: chr7-117230490;