NM_000492.4(CFTR):c.330C>A (p.Asp110Glu) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000577359.14

Allele description [Variation Report for NM_000492.4(CFTR):c.330C>A (p.Asp110Glu)]

NM_000492.4(CFTR):c.330C>A (p.Asp110Glu)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.330C>A (p.Asp110Glu)

HGVS:

NC_000007.14:g.117530955C>A
NG_016465.4:g.70172C>A
NM_000492.4:c.330C>AMANE SELECT
NP_000483.3:p.Asp110Glu
NP_000483.3:p.Asp110Glu
LRG_663t1:c.330C>A
LRG_663:g.70172C>A
LRG_663p1:p.Asp110Glu
NC_000007.13:g.117171009C>A
NM_000492.3:c.330C>A

Protein change:

D110E

Links:

PharmGKB: 1449191401PA165950341; dbSNP: rs397508537

NCBI 1000 Genomes Browser:

rs397508537

Molecular consequence:

NM_000492.4:c.330C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679435	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000696964	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 17, 2020)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 11354633, 11883825, 12752573, 22326559, 23891399, 24813944, 20538955, 25735457, 26471113, 26847993, 10790222, 26684250, 29805046, 25024266, 30888834 Citation Link,
SCV001589606	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 25, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10790222, 11883825, 23891399, 29805046, 9272157, 18373402, 19897426, 22724884, 28492532
SCV002606446	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10790222, 11883825, 22326559, 23891399, 25024266, 25735457, 26471113, 26847993, 29805046, 29812963, 30561903, 31328366 Citation Link,
SCV005052060	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease.

Tzetis M, Efthymiadou A, Strofalis S, Psychou P, Dimakou A, Pouliou E, Doudounakis S, Kanavakis E.

Hum Genet. 2001 Mar;108(3):216-21.

PubMed [citation]

PMID:: 11354633

Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2.

Zhou T, Xiong J, Wang M, Yang N, Wong J, Zhu B, Xu RM.

Mol Cell. 2014 Jun 5;54(5):879-86. doi: 10.1016/j.molcel.2014.04.003. Epub 2014 May 8.

PubMed [citation]

PMID:: 24813944

See all PubMed Citations (26)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679435.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000796470.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001589606.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002606446.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005052060.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796470	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 14, 2017)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11810271, 10790222, 12752573, 25024266, 17272608, 23891399, 22326559, 20538955 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000796470

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Dec 14, 2017)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Last Updated: Sep 29, 2024

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