7-117530955-C-A

Position:

chr7-117530955-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Strong

The NM_000492.4(CFTR):c.330C>A(p.Asp110Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,498 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 drug response (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D110H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:8U:1O:2

Conservation

PhyloP100: -0.359

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS1

Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 3019253

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain 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 chr7-117530953-G-C is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 7108.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 7-117530955-C-A is Pathogenic according to our data. Variant chr7-117530955-C-A is described in ClinVar as [drug_response]. Clinvar id is 53714.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=2, Uncertain_significance=1, not_provided=1, drug_response=1}. Variant chr7-117530955-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.330C>A	p.Asp110Glu	missense_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.330C>A	p.Asp110Glu	missense_variant	4/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251104

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135686

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727038

show subpopulations

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: drug response

Submissions summary: Pathogenic:8Uncertain:1Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2023	The p.D110E variant (also known as c.330C>A), located in coding exon 4 of the CFTR gene, results from a C to A substitution at nucleotide position 330. The aspartic acid at codon 110 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been identified in multiple individuals, including one homozygous individual with borderline sweat chloride levels and no lung disease (Padoan R et al. Hum. Mutat., 2000 May;15:485; Padoan R et al. Acta Paediatr, 2002;91:82-7; Poulou M et al. J. Cyst. Fibros., 2012 Jul;11:344-8). Functional studies demonstrated that this variant results in reduced CFTR channel function, compared to wild-type protein (Cui G et al. J. Gen. Physiol., 2014 Aug;144:159-79; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Dec 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 110 of the CFTR protein (p.Asp110Glu). This variant is present in population databases (rs397508537, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10790222, 11883825). ClinVar contains an entry for this variant (Variation ID: 53714). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 29805046). This variant disrupts the p.Asp110 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272157, 18373402, 19897426, 22724884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2020	Variant summary: CFTR c.330C>A (p.Asp110Glu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 1.6e-05 in 251104 control chromosomes (gnomAD). c.330C>A has been reported in the literature in multiple individuals affected with varying phenotypes, predominantly presenting as a mild phenotype, which patients have a borderline sweat chloride level, pancreatic sufficiency, and normal lung function (Colombo_2006, Padoan_2002, Sermet-Gaudelus__2010, Tzetis_2001, Xie_2015, McCague_2019). These data indicate that the variant is very likely to be associated with disease. However, functional studies have indicated that the variant greater affects chloride transport (van Goor_2013, Raraigh_2018) and significantly longer mean burst durations (Cui_2014 and Infield_2016). Authors further go on to state "the structure of ECL1 must be tuned delicately to maintain function...none of the charge-retaining mutations identified in ECL1 are able to completely rescue the mutant channel behavior to that of WT-CFTR. This is likely the result of a requirement for very specific bond angles within a network of charged residues that control the architecture of ECL1"(Cui_2014)." Furthermore, another variant at this location D110H has been classified as "pathogenic" by LCA, along with another variant being reported D110R (Cui_2014), therefore, suggesting this location is a mutational hotspot and important for protein function. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cystic fibrosis;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Mar 09, 2018

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 23, 2017

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 05, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D;.;.;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.81

.;L;.;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.8

D;N;.;.;N;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

D;T;.;.;T;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

0.97

.;D;.;.;.;.

Vest4

0.95

MutPred

0.83

.;Gain of ubiquitination at K114 (P = 0.0467);Gain of ubiquitination at K114 (P = 0.0467);Gain of ubiquitination at K114 (P = 0.0467);Gain of ubiquitination at K114 (P = 0.0467);Gain of ubiquitination at K114 (P = 0.0467);

MVP

0.99

MPC

0.0045

ClinPred

0.78

GERP RS

0.88

Varity_R

0.40

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over