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NM_000492.4(CFTR):c.490A>G (p.Thr164Ala) AND not specified

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 15, 2019
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:
RCV000780137.9

Allele description [Variation Report for NM_000492.4(CFTR):c.490A>G (p.Thr164Ala)]

NM_000492.4(CFTR):c.490A>G (p.Thr164Ala)

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.490A>G (p.Thr164Ala)
HGVS:
  • NC_000007.14:g.117534276A>G
  • NG_016465.4:g.73493A>G
  • NM_000492.4:c.490A>GMANE SELECT
  • NP_000483.3:p.Thr164Ala
  • NP_000483.3:p.Thr164Ala
  • LRG_663t1:c.490A>G
  • LRG_663:g.73493A>G
  • LRG_663p1:p.Thr164Ala
  • NC_000007.13:g.117174330A>G
  • NM_000492.3:c.490A>G
  • NM_000492.4:c.490A>G
  • p.Thr164Ala
Protein change:
T164A
Links:
dbSNP: rs200885306
NCBI 1000 Genomes Browser:
rs200885306
Molecular consequence:
  • NM_000492.4:c.490A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000917182Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Dec 13, 2018) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001160242ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Uncertain significance
(Jan 15, 2019) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917182.1

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

Description

Variant summary: CFTR c.490A>G (p.Thr164Ala) results in a non-conservative amino acid change of the first nucleotide of exon 5, located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 275348 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.490A>G in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160242.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CFTR c.490A>G; p.Thr164Ala variant (rs200885306), to our knowledge, is not reported in the medical literature but is reported in the Sick Kids CFTR database (see link). This variant is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 164 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr164Ala variant is uncertain at this time. References: Link to Sick Kids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html

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

Last Updated: Nov 24, 2024