NM_000492.4(CFTR):c.1454G>C (p.Ser485Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 12, 2023
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:: RCV001001194.12

Allele description [Variation Report for NM_000492.4(CFTR):c.1454G>C (p.Ser485Thr)]

NM_000492.4(CFTR):c.1454G>C (p.Ser485Thr)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1454G>C (p.Ser485Thr)

Other names:

p.Ser485Thr

HGVS:

NC_000007.14:g.117559525G>C
NG_016465.4:g.98742G>C
NM_000492.4:c.1454G>CMANE SELECT
NP_000483.3:p.Ser485Thr
NP_000483.3:p.Ser485Thr
LRG_663t1:c.1454G>C
LRG_663:g.98742G>C
LRG_663p1:p.Ser485Thr
NC_000007.13:g.117199579G>C
NM_000492.3:c.1454G>C
NM_000492.4:c.1454G>C

Protein change:

S485T

Links:

dbSNP: rs143980575

NCBI 1000 Genomes Browser:

rs143980575

Molecular consequence:

NM_000492.4:c.1454G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360595	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25735457, 29669919, 31311920 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360595

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 12, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations.

Ramalho AS, Clarke LA, Sousa M, Felicio V, Barreto C, Lopes C, Amaral MD.

J Cyst Fibros. 2016 Jan;15(1):21-33. doi: 10.1016/j.jcf.2015.02.002. Epub 2015 Feb 27.

PubMed [citation]

PMID:: 25735457

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer.

Tamura K, Yu J, Hata T, Suenaga M, Shindo K, Abe T, MacGregor-Das A, Borges M, Wolfgang CL, Weiss MJ, He J, Canto MI, Petersen GM, Gallinger S, Syngal S, Brand RE, Rustgi A, Olson SH, Stoffel E, Cote ML, Zogopoulos G, Potash JB, et al.

Proc Natl Acad Sci U S A. 2018 May 1;115(18):4767-4772. doi: 10.1073/pnas.1720588115. Epub 2018 Apr 18.

PubMed [citation]

PMID:: 29669919
PMCID:: PMC5939087

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360595.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: CFTR c.1454G>C (p.Ser485Thr) results in a conservative amino acid change located in the ABC transporter-like (IPR003439)and AAA+ ATPase domain (IPR003593) 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 5.2e-05 in 251332 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (5.2e-05 vs 0.013), allowing no conclusion about variant significance. c.1454G>C has been reported in the literature in individuals affected with pancreatic cancer and pancreatitis (Tamura _2018, Shik Mun _2019). These reports 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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

Last Updated: Sep 29, 2024

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