NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr) AND Cystic fibrosis

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 20, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000046494.7

Allele description [Variation Report for NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr)]

NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr)

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.1853T>C (p.Ile618Thr)
HGVS:
  • NC_000007.14:g.117592020T>C
  • NG_016465.4:g.131237T>C
  • NM_000492.3:c.1853T>C
  • NM_000492.4:c.1853T>CMANE SELECT
  • NP_000483.3:p.Ile618Thr
  • NP_000483.3:p.Ile618Thr
  • LRG_663t1:c.1853T>C
  • LRG_663:g.131237T>C
  • LRG_663p1:p.Ile618Thr
  • NC_000007.13:g.117232074T>C
  • P13569:p.Ile618Thr
Protein change:
I618T
Links:
UniProtKB: P13569#VAR_000202; dbSNP: rs139468767
NCBI 1000 Genomes Browser:
rs139468767
Molecular consequence:
  • NM_000492.3:c.1853T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000492.4:c.1853T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696878Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Nov 20, 2020)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV000886317Mendelicscriteria provided, single submitter
Pathogenic
(Nov 5, 2018)
unknownclinical testing

Citation Link,

SCV000886895Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Likely pathogenic
(Mar 1, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001576371Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 11, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

http://www.genet.sikkids.on.a/

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Phenotype prediction of non-synonymous single-nucleotide polymorphisms in human ATP-binding cassette transporter genes.

Wang LL, Liu YH, Meng LL, Li CG, Zhou SF.

Basic Clin Pharmacol Toxicol. 2011 Feb;108(2):94-114. doi: 10.1111/j.1742-7843.2010.00627.x. Epub 2010 Sep 6.

PubMed [citation]
PMID:
20849526

Genetic interaction of GSH metabolic pathway genes in cystic fibrosis.

de Lima Marson FA, Bertuzzo CS, Secolin R, Ribeiro AF, Ribeiro JD.

BMC Med Genet. 2013 Jun 10;14:60. doi: 10.1186/1471-2350-14-60.

PubMed [citation]
PMID:
23758905
PMCID:
PMC3685592
See all PubMed Citations (15)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696878.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 3.8e-05 in 262104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (3.8e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.1853T>C, has been reported in the literature in compound heterozygosity with p.F508del or p.G542X in at-least two individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012). These data indicate that the variant may be associated with disease although multiple publications reporting the same patients confound distinct ascertainment (example, Vankeerberghen_1998, Marson_2012A, Marson_2013, Guimbellot_2017, Goncalves_2018, Pereira_2019). Additionally, this variant has been observed in compound heterozygosity with other classic CFTR mutations such as p.A559T (c.1675G>A), p.F508del (c.1521_1523delCTT) and p.Ser1255X (c.3764C>A) in at-least three patients (a pair of sibs and two other distinct patients) sequenced for the CFTR gene at our laboratory. Detailed clinical information was available on one of these patients who was confirmed to have a known diagnosis of pancreatically insufficient CF with elevated sweat chloride levels, positivity for CF pathogens, severe baseline lung disease, and sinusitis. As the compound heterozygous genotypes observed in our laboratory are distinct (p.A559T and p.Ser1255X) from those reported in the literature, these data indicate that the variant is likely to be associated with disease (ACMG PP4). One publication, Pasyk_1998, reported this variant exhibits <50% of normal activity as chloride channel (ACMG PS3) while another publication, Vankeerberghen_1998, not providing primary data, reported this variant as resulting in abnormal processing leading to no or minimal functional CFTR proteins appearing at the cell membranes. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic (n=1), Pathogenic (n=2)). Based on the evidence outlined above, the variant was classified as likely pathogenic until additional clinical and functional evidence become available.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV000886317.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV000886895.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This CFTR variant (rs139468767) has been previously reported and is rare in large population datasets (gnomAD: 10/261916 total alleles; 0.003818%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as pathogenic and a third as a variant of uncertain clinical significance. Independent functional studies determined that this protein does not mature into its fully glycosylated state. Additionally, if any protein is properly trafficked, it is predicted to have reduced chloride conductance. This variant is considered likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001576371.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces isoleucine with threonine at codon 618 of the CFTR protein (p.Ile618Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs139468767, ExAC 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 9150159, 23857699, http://www.genet.sickkids.on.ca/, external communication). This variant is also known as c.1985T>C. ClinVar contains an entry for this variant (Variation ID: 53404). This variant has been reportedto affect CFTR protein function (PMID: 9822639, 9736778). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

Support Center