NM_000243.3(MEFV):c.2263A>G (p.Ile755Val) AND Familial Mediterranean fever

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 8, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000083759.8

Allele description [Variation Report for NM_000243.3(MEFV):c.2263A>G (p.Ile755Val)]

NM_000243.3(MEFV):c.2263A>G (p.Ile755Val)

Gene:

MEFV:MEFV innate immunity regulator, pyrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000243.3(MEFV):c.2263A>G (p.Ile755Val)

HGVS:

NC_000016.10:g.3243224T>C
NG_007871.1:g.18404A>G
NM_000243.3:c.2263A>GMANE SELECT
NM_001198536.2:c.*467A>G
NP_000234.1:p.Ile755Val
NP_000234.1:p.Ile755Val
LRG_190t1:c.2263A>G
LRG_190:g.18404A>G
LRG_190p1:p.Ile755Val
NC_000016.9:g.3293224T>C
NM_000243.1:c.2263A>G
NM_000243.2:c.2263A>G

Protein change:

I755V

Links:

dbSNP: rs104895194

NCBI 1000 Genomes Browser:

rs104895194

Molecular consequence:

NM_001198536.2:c.*467A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.2263A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial Mediterranean fever (FMF)
Synonyms:: POLYSEROSITIS, FAMILIAL PAROXYSMAL; POLYSEROSITIS, RECURRENT; Periodic peritonitis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018088; MedGen: C0031069; Orphanet: 342; OMIM: 249100

Recent activity

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PREDICTED: Homo sapiens zinc finger protein 444 (ZNF444), transcript variant X1,...
PREDICTED: Homo sapiens zinc finger protein 444 (ZNF444), transcript variant X1, mRNA
gi|2217321855|ref|XM_024451573.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000115854	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV001199916	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21520333, 28492532
SCV001462091	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV003802356	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Feb 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000115854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001199916.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 755 of the MEFV protein (p.Ile755Val). This variant is present in population databases (rs104895194, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 97507). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

From Natera, Inc., SCV001462091.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Genome-Nilou Lab, SCV003802356.1

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

#	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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