NM_000243.3(MEFV):c.1223G>A (p.Arg408Gln) AND Familial Mediterranean fever

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV000002661.39

Allele description [Variation Report for NM_000243.3(MEFV):c.1223G>A (p.Arg408Gln)]

NM_000243.3(MEFV):c.1223G>A (p.Arg408Gln)

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.1223G>A (p.Arg408Gln)

Other names:

R408Q

HGVS:

NC_000016.10:g.3249468C>T
NG_007871.1:g.12160G>A
NM_000243.3:c.1223G>AMANE SELECT
NM_001198536.2:c.590G>A
NP_000234.1:p.Arg408Gln
NP_000234.1:p.Arg408Gln
NP_001185465.2:p.Arg197Gln
LRG_190t1:c.1223G>A
LRG_190:g.12160G>A
LRG_190p1:p.Arg408Gln
NC_000016.9:g.3299468C>T
NM_000243.2:c.1223G>A
O15553:p.Arg408Gln

Protein change:

R197Q; ARG408GLN

Links:

UniProtKB: O15553#VAR_009056; OMIM: 608107.0015; dbSNP: rs11466024

NCBI 1000 Genomes Browser:

rs11466024

Molecular consequence:

NM_000243.3:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001198536.2:c.590G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022819	OMIM	no assertion criteria provided	Uncertain significance (Jan 1, 2013)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10364520, 22995991
SCV000484961	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000629018	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001277732	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10364520, 19934082, 10090880 Citation Link,
SCV001623488	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580762	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 23, 2022)	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	yes	3	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

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

Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein.

Ryan JG, Masters SL, Booty MG, Habal N, Alexander JD, Barham BK, Remmers EF, Barron KS, Kastner DL, Aksentijevich I.

Ann Rheum Dis. 2010 Jul;69(7):1383-8. doi: 10.1136/ard.2009.113415. Epub 2009 Nov 23.

PubMed [citation]

PMID:: 19934105
PMCID:: PMC3570240

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000022819.5

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

Description

This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (249100), has been reclassified based on the findings of Berg et al. (2013).

In a genotypic study of 90 Armenian FMF (249100) patients from 77 unrelated families, Cazeneuve et al. (1999) identified a novel mutation, arg408-to-gln (R408Q) in the MEFV gene. The mutation was identified in 1 patient in cis with the E148Q (608107.0005) and P369S (608107.0014) mutations.

Berg et al. (2013) reclassified the R408Q mutation as 'considered to imply carrier status' for a recessive disorder. They noted that the R408Q and P369S (608107.0014) mutations had been reported in cis as a single allele resulting in a highly variable clinical phenotype.

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

From GeneReviews, SCV000484961.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629018.9

#	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

From Illumina Laboratory Services, Illumina, SCV001277732.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 Genome-Nilou Lab, SCV001623488.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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