rs397508537

Variant names:

• chr7-117530955-C-A
• rs397508537
• NM_000492.4:c.330C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117530955-C-A
• chr7-117530955-C-G
• chr7-117530955-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM1 PM5 PP2 PP3_Moderate

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 the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D110V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:8 U:1 O:2
• Conservation: PhyloP100: -0.359
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117530954-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1729921.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.330C>A	p.Asp110Glu	missense_variant	Exon 4 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.330C>A	p.Asp110Glu	missense_variant	Exon 4 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251104 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461498 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: drug response

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

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 14, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 17, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

CFTR-related disorder Pathogenic:1

Sep 05, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 23, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Mar 09, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

ivacaftor response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;.;.;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	.;L;.;.;.;L
PhyloP100		-0.36
PrimateAI	Uncertain	0.72	T
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	D
GERP RS		0.88
Varity_R		0.40
gMVP		0.83
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs397508537; hg19: chr7-117171009;