NM_000243.3(MEFV):c.586G>T (p.Gly196Trp) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jul 3, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000587560.5

Allele description [Variation Report for NM_000243.3(MEFV):c.586G>T (p.Gly196Trp)]

NM_000243.3(MEFV):c.586G>T (p.Gly196Trp)

Gene:
MEFV:MEFV innate immuity regulator, pyrin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p13.3
Genomic location:
Preferred name:
NM_000243.3(MEFV):c.586G>T (p.Gly196Trp)
HGVS:
  • NC_000016.10:g.3254482C>A
  • NG_007871.1:g.7146G>T
  • NM_000243.2:c.586G>T
  • NM_000243.3:c.586G>TMANE SELECT
  • NM_001198536.2:c.277+1829G>T
  • NP_000234.1:p.Gly196Trp
  • NP_000234.1:p.Gly196Trp
  • LRG_190t1:c.586G>T
  • LRG_190:g.7146G>T
  • LRG_190p1:p.Gly196Trp
  • NC_000016.9:g.3304482C>A
  • NM_000243.1:c.586G>T
  • O15553:p.Gly196Trp
Protein change:
G196W
Links:
UniProtKB: O15553#VAR_072382; dbSNP: rs104895179
NCBI 1000 Genomes Browser:
rs104895179
Molecular consequence:
  • NM_001198536.2:c.277+1829G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000243.2:c.586G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000243.3:c.586G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000279039GeneDxcriteria provided, single submitter
Likely benign
(Jul 3, 2019)
germlineclinical testing

Citation Link,

SCV000696076Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jul 20, 2016)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

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

Citations

PubMed

An informatics approach to analyzing the incidentalome.

Berg JS, Adams M, Nassar N, Bizon C, Lee K, Schmitt CP, Wilhelmsen KC, Evans JP.

Genet Med. 2013 Jan;15(1):36-44. doi: 10.1038/gim.2012.112. Epub 2012 Sep 20.

PubMed [citation]
PMID:
22995991
PMCID:
PMC3538953

Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey.

Oztuzcu S, Ulaşlı M, Ergun S, Iğci YZ, Iğci M, Bayraktar R, Nacarkahya G, Tamer A, Cevik MO, Cakmak EA, Arslan A.

Mol Biol Rep. 2014;41(4):2601-7. doi: 10.1007/s11033-014-3118-5. Epub 2014 Jan 28.

PubMed [citation]
PMID:
24469716
See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000279039.9

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29178647, 26990548, 22995991, 20044784, 24929125, 24263150, 32199921)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696076.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant Summary: The MEFV variant, c.586G>T (p.Gly196Trp), causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.20%, predominantly observed in the African subpopulation at a frequency of 2.4%. This frequency slightly exceeds the maximal expected allele frequency for a pathogenic variant in MEFV (2.2%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in at least 2 FMF patients, one of whom also had a common pathogenic mutation in the homozygous state (c.2082G>A, M694I; Gunesacar_2014), suggesting the variant of interest was not the causitive mutation in this individual. The variant has also been reported in atypical FMF patients and a Systemic Juvenile Idiopathic Arthritis patient, however the variant was the only detected variant in these patients. In addition, one reputable clinical lab has classified the variant as "benign", without evidence to independently evaluate. Taken together, this variant has been classified as a variant of uncertain significance, possibly benign variant, until additional information becomes available.

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

Last Updated: Nov 27, 2021

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