NM_000243.3(MEFV):c.2082G>A (p.Met694Ile) AND not provided

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Mar 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000220431.50

Allele description [Variation Report for NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)]

NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)

Genes:

LOC126862264:CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:3293322-3294521 [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.2082G>A (p.Met694Ile)

Other names:

M694I

HGVS:

NC_000016.10:g.3243405C>T
NG_007871.1:g.18223G>A
NM_000243.3:c.2082G>AMANE SELECT
NM_001198536.2:c.*286G>A
NP_000234.1:p.Met694Ile
NP_000234.1:p.Met694Ile
LRG_190t1:c.2082G>A
LRG_190:g.18223G>A
LRG_190p1:p.Met694Ile
NC_000016.9:g.3293405C>T
NM_000243.2:c.2082G>A
O15553:p.Met694Ile
c.2082G>A (p.Met694Ile)

Protein change:

MET694ILE

Links:

UniProtKB: O15553#VAR_009061; OMIM: 608107.0002; OMIM: 608107.0018; dbSNP: rs28940578

NCBI 1000 Genomes Browser:

rs28940578

Molecular consequence:

NM_001198536.2:c.*286G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.2082G>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
SCV000279059	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 15, 2020)	germline	clinical testing	Citation Link,
SCV000280932	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 22, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000604182	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Dec 28, 2022)	germline	clinical testing	Citation Link,
SCV000854900	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 10, 2017)	germline	clinical testing	Citation Link,
SCV001245669	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001450267	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001480074	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001798514	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001929663	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	Pathogenic	germline	clinical testing
SCV001951693	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001976076	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	Pathogenic	germline	clinical testing
SCV002017259	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226902	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 15, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10024914, 10612841, 10787449, 11938447, 12064853, 24318677, 32398039, 33733382, 34880353, 9288094, 9781020, 25741868 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	36	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	3	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	clinical testing

Citations

PubMed

Pyrin/marenostrin mutations in familial Mediterranean fever.

Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN.

QJM. 1998 Sep;91(9):603-6.

PubMed [citation]

PMID:: 10024914

MEFV mutations in Turkish patients suffering from Familial Mediterranean Fever.

Akar N, Misiroglu M, Yalcinkaya F, Akar E, Cakar N, Tümer N, Akcakus M, Tastan H, Matzner Y.

Hum Mutat. 2000 Jan;15(1):118-9.

PubMed [citation]

PMID:: 10612841

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000279059.8

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

Description

Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876)

#	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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280932.1

#	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	not provided	not provided	not provided	not provided		not provided	0.000112	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604182.10

#	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.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647

#	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 Eurofins Ntd Llc (ga), SCV000854900.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245669.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	24	not provided	not provided	clinical testing	not provided

Description

MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4

#	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		24	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450267.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	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		12	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001480074.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001798514.1

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001929663.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951693.1

#	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, SCV001976076.1

#	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 Revvity Omics, Revvity, SCV002017259.3

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (12)

Description

PP1, PM1, PM3_very_strong, PM5, PS3, PS4

#	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		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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