NM_000243.3(MEFV):c.986G>A (p.Arg329His) AND not provided

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:: RCV000585083.52

Allele description [Variation Report for NM_000243.3(MEFV):c.986G>A (p.Arg329His)]

NM_000243.3(MEFV):c.986G>A (p.Arg329His)

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.986G>A (p.Arg329His)

HGVS:

NC_000016.10:g.3249705C>T
NG_007871.1:g.11923G>A
NM_000243.3:c.986G>AMANE SELECT
NM_001198536.2:c.353G>A
NP_000234.1:p.Arg329His
NP_000234.1:p.Arg329His
NP_001185465.2:p.Arg118His
LRG_190t1:c.986G>A
LRG_190:g.11923G>A
LRG_190p1:p.Arg329His
NC_000016.9:g.3299705C>T
NM_000243.1:c.986G>A
NM_000243.2:c.986G>A

Protein change:

R118H

Links:

dbSNP: rs104895112

NCBI 1000 Genomes Browser:

rs104895112

Molecular consequence:

NM_000243.3:c.986G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001198536.2:c.353G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279045	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 27, 2023)	germline	clinical testing	Citation Link,
SCV000338237	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Jul 13, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22903357, 20041150, 26620106 Citation Link,
SCV000604184	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Feb 28, 2022)	germline	clinical testing	Citation Link,
SCV000692832	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Feb 1, 2024)	germline	clinical testing	Citation Link,
SCV001978057	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001980598	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population.

Lainka E, Bielak M, Lohse P, Timmann C, Stojanov S, von Kries R, Niehues T, Neudorf U.

Eur J Pediatr. 2012 Dec;171(12):1775-85. doi: 10.1007/s00431-012-1803-8. Epub 2012 Aug 19.

PubMed [citation]

PMID:: 22903357

Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels.

Feng J, Zhang Z, Li W, Shen X, Song W, Yang C, Chang F, Longmate J, Marek C, St Amand RP, Krontiris TG, Shively JE, Sommer SS.

PLoS One. 2009 Dec 30;4(12):e8480. doi: 10.1371/journal.pone.0008480.

PubMed [citation]

PMID:: 20041150
PMCID:: PMC2794536

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000279045.13

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

Description

Reported in the heterozygous state in multiple unrelated individuals with familial Mediterranean fever (Feng et al., 2009; Lainka et al., 2012; Yao et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26554556, 26247045, 22903357, 29260407, 26620106, 23010357, 23325590, 24117178, 20041150, 29178647, 27838405, 29408806, 23867542, 23070486, 22337722, 31989427, 32271453, 30755392, 35156637)

#	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 Eurofins Ntd Llc (ga), SCV000338237.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

#	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		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604184.9

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

Description

The MEFV c.986G>A; p.Arg329His variant (rs104895112) has been described in the literature in several individuals affected with familial Mediterranean fever (FMF), atypical FMF, or fibromyalgia (Lainka 2012, Feng 2009, Portincasa 2013, Yao 2016). This variant is listed in ClinVar (Variation ID: 97557) and is found in the general population with an overall allele frequency of 0.16% (441/279644 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at position 329 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.166). Due to the wide range of phenyotypes and lack of functional data, the significance of the p.Arg329His variant is uncertain at this time. References: Lainka E et al. Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population. Eur J Pediatr. 2012 Dec;171(12):1775-85. PMID: 22903357. Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009. 4(12):e8480. PMID: 20041150. Portincasa P et al. Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder. Eur J Clin Invest. 2013 Dec;43(12):1314-27. PMID: 24117178. Yao Q et al. Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. Semin Arthritis Rheum. 2016 Apr;45(5):633-7. PMID: 26620106.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV000692832.30

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

MEFV: BP4, BS1

#	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		6	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001978057.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001980598.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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