7-117530953-G-C

Position:

chr7-117530953-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.328G>C(p.Asp110His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,670 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 Pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D110E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:17O:2

Conservation

PhyloP100: 9.52

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 18 ACMG points.

PM1

In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) 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 chr7-117530955-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 7-117530953-G-C is Pathogenic according to our data. 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. Variant chr7-117530953-G-C is described in Lovd as [Pathogenic]. Variant chr7-117530953-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.328G>C	p.Asp110His	missense_variant	4/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.328G>C	p.Asp110His	missense_variant	4/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251100

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000178

AC:

AN:

1461508

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:17Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2023	The p.D110H pathogenic mutation (also known as c.328G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 328. The aspartic acid at codon 110 is replaced by histidine, an amino acid with similar properties. This mutation was first described in a child with elevated sweat chloride levels and p.F508del confirmed in trans (Dean M et al. Cell, 1990 Jun;61:863-70). Another study described a homozygous Turkish male who presented with congenital bilateral absence of the vas deferens (CBAVD), asthma bronchiale, and obstipation (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Functional data showed a reduced level of CFTR protein and 9% chloride activity compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Another study suggested that this mutation disrupts the chloride channel activity by destabilizing the open state of the CFTR protein (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). In addition, this mutation is associated with pancreatic sufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). An alteration at the same amino acid position, p.D110E, was also described in a child with elevated sweat chloride levels and pancreatic sufficiency (Padoan R et al. Hum. Mutat., 2000 May;15:485). 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 the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 02, 2023	Criteria applied: PM5_STR,PS3_MOD,PM1,PM3,PM2_SUP,PP3 -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 05, 2014	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 27, 2022	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 110 of the CFTR protein (p.Asp110His). This variant is present in population databases (rs113993958, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2344617, 9272157, 18373402, 19897426, 20059485, 20949073, 22724884, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7108). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 23891399). For these reasons, this variant has been classified as Pathogenic. -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 20, 2019	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 20, 2017

Variant summary: The CFTR c.328G>C (p.Asp110His) variant involves the alteration of a conserved nucleotide that is located in the ABC transporter type 1, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/245956 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). Compound heterozygotes and homozygotes for this variant have been found in numerous patients with CBAVD, CF, and in pt with clinical findings suggestive of CF. A functional study showed that baseline chloride transport in CFTR-D110H transfected FRT cells was 9.1% of that in WT-CFTR transfected FRT cells (Van Goor_2013), indicating that D110H significantly affects normal function of CFTR. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Hereditary pancreatitis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

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

not provided

Other:1

not provided, no classification provided

literature only

SNPedia

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;D;.;.;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

.;M;.;.;.;M

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.5

D;N;.;.;N;.

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.98

MutPred

0.89

.;Gain of ubiquitination at K114 (P = 0.0872);Gain of ubiquitination at K114 (P = 0.0872);Gain of ubiquitination at K114 (P = 0.0872);Gain of ubiquitination at K114 (P = 0.0872);Gain of ubiquitination at K114 (P = 0.0872);

MVP

1.0

MPC

0.0052

ClinPred

0.64

GERP RS

5.7

Varity_R

0.85

gMVP

0.93

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