NM_000492.4(CFTR):c.1365G>A (p.Ala455=) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Oct 11, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000588680.4

Allele description [Variation Report for NM_000492.4(CFTR):c.1365G>A (p.Ala455=)]

NM_000492.4(CFTR):c.1365G>A (p.Ala455=)

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.1365G>A (p.Ala455=)
HGVS:
  • NC_000007.14:g.117548796G>A
  • NG_016465.4:g.88013G>A
  • NM_000492.3:c.1365G>A
  • NM_000492.4:c.1365G>AMANE SELECT
  • NP_000483.3:p.Ala455=
  • NP_000483.3:p.Ala455=
  • LRG_663t1:c.1365G>A
  • LRG_663:g.88013G>A
  • LRG_663p1:p.Ala455=
  • NC_000007.13:g.117188850G>A
Links:
dbSNP: rs79074685
NCBI 1000 Genomes Browser:
rs79074685
Molecular consequence:
  • NM_000492.3:c.1365G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_000492.4:c.1365G>A - synonymous variant - [Sequence Ontology: SO:0001819]
Observations:
9

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696838Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Apr 25, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000700537EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Oct 11, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown9not providednot providednot providednot providedclinical testing

Citations

PubMed

Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.

Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A.

J Mol Diagn. 2005 May;7(2):289-99.

PubMed [citation]
PMID:
15858154
PMCID:
PMC1867528

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696838.1

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

Description

Variant summary: The c.1365G>A (p.Ala455Ala) variant affects a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions are not validated by in vivo/vitro experimental studies yet. The variant of interest has been observed in one case with limited phenotypic information (Shrijver_2005). In addition, the c.1365G>A variant have been found in two internal cases in homozygous condition. Both were presumably healthy women of reproductive age undergoing routine carrier screening. The variant has been reported mainly in African controls:1. The prevalence of CF in Africans is 1/15000, and the attributable risk of all non-common variants about 0.2, which makes the maximal allele frequency of all non-common pathogenic variants approximately 1:750 (Based on Rohlfs_CC_2011). The variant was found in 37/7216 African chromosomes in ExAC (1:196), which is consistent with benign nature of the variant.2. The c.2988+1G>A and p.F508del variants are two most frequent pathogenic variants in Africans (up to 61% of all carriers, Rohlfs et al, 2011). The combined allele frequencies of these two variants in the African cohort from the ExAC database is 0.29% (30/10338). The p.Ala455Ala was found 37 times in 7216 African chromosomes in the same ExAC African cohort (0.51%). So the frequency of c.1365G>A alone is much higher than combined frequency of two most common pathogenic variants in the same cohort.Taken together, this variant is classified as likely benign.

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

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000700537.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided9not providednot providednot provided

Last Updated: Nov 6, 2021

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