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NM_000492.4(CFTR):c.374T>C (p.Ile125Thr) AND not specified

Germline classification:
Likely benign (2 submissions)
Last evaluated:
Jan 15, 2022
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:
RCV000595646.14

Allele description [Variation Report for NM_000492.4(CFTR):c.374T>C (p.Ile125Thr)]

NM_000492.4(CFTR):c.374T>C (p.Ile125Thr)

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.374T>C (p.Ile125Thr)
HGVS:
  • NC_000007.14:g.117530999T>C
  • NG_016465.4:g.70216T>C
  • NM_000492.4:c.374T>CMANE SELECT
  • NP_000483.3:p.Ile125Thr
  • NP_000483.3:p.Ile125Thr
  • LRG_663t1:c.374T>C
  • LRG_663:g.70216T>C
  • LRG_663p1:p.Ile125Thr
  • NC_000007.13:g.117171053T>C
  • NM_000492.3:c.374T>C
Protein change:
I125T
Links:
dbSNP: rs141723617
NCBI 1000 Genomes Browser:
rs141723617
Molecular consequence:
  • NM_000492.4:c.374T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696986Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely benign
(Jan 15, 2022)
germlineclinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link,

SCV000706922Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Likely benign
(Mar 13, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing

Citations

PubMed

A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.

Lee JH, Choi JH, Namkung W, Hanrahan JW, Chang J, Song SY, Park SW, Kim DS, Yoon JH, Suh Y, Jang IJ, Nam JH, Kim SJ, Cho MO, Lee JE, Kim KH, Lee MG.

Hum Mol Genet. 2003 Sep 15;12(18):2321-32.

PubMed [citation]
PMID:
12952861

Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis.

Chang MC, Chang YT, Wei SC, Tien YW, Liang PC, Jan IS, Su YN, Wong JM.

Clin Genet. 2007 Jun;71(6):530-9.

PubMed [citation]
PMID:
17539902
See all PubMed Citations (17)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696986.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (17)

Description

Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-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 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.

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

From Eurofins Ntd Llc (ga), SCV000706922.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Jul 15, 2024