chr7-117591993-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000492.4(CFTR):​c.1826A>T​(p.His609Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H609R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CFTR
NM_000492.4 missense

Scores

7
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 8.60
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-117591993-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959
PP5
Variant 7-117591993-A-T is Pathogenic according to our data. Variant chr7-117591993-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53399.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.1826A>T p.His609Leu missense_variant Exon 14 of 27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.1826A>T p.His609Leu missense_variant Exon 14 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:1Uncertain:2
Oct 18, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. This variant disrupts the p.His609 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16189704, 19457724). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 53399). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 21520337, 25910067, 31005549). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 609 of the CFTR protein (p.His609Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. -

Jul 22, 2021
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CFTR c.1826A>T (p.His609Leu) variant is a missense variant that has been reported in a compound heterozygous state with an intronic variant in one individual with congenital bilateral absence of the vas deferens (CBAVD) (Steiner et al. 2011). The p.His609Leu variant was absent from 319 controls. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being found in a region of good sequencing coverage. Therefore, it is presumed to be rare. Based on the limited evidence, the p.His609Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:2
Dec 27, 2016
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 15, 2023
Revvity Omics, Revvity
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
Benign
0.24
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.73
D;.;T;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
-0.36
N;.;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-2.4
N;.;N;.
REVEL
Pathogenic
0.75
Sift
Benign
0.49
T;.;T;.
Sift4G
Uncertain
0.011
D;.;D;.
Polyphen
0.99
D;.;.;.
Vest4
0.83
MutPred
0.91
Loss of disorder (P = 0.052);.;.;.;
MVP
0.97
MPC
0.0038
ClinPred
0.90
D
GERP RS
5.5
Varity_R
0.71
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397508310; hg19: chr7-117232047; COSMIC: COSV50068019; COSMIC: COSV50068019; API