NM_000243.2(MEFV):c.2080A>G (p.Met694Val) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 6, 2018
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:: RCV000216751.5

Allele description

NM_000243.2(MEFV):c.2080A>G (p.Met694Val)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000243.2(MEFV):c.2080A>G (p.Met694Val)

Other names:

NM_000243.2(MEFV):c.2080A>G(p.Met694Val)

HGVS:

NC_000016.10:g.3243407T>C
NG_007871.1:g.18221A>G
NM_000243.2:c.2080A>G
NM_001198536.1:c.*284A>G
NP_000234.1:p.Met694Val
NP_000234.1:p.Met694Val
LRG_190t1:c.2080A>G
LRG_190:g.18221A>G
LRG_190p1:p.Met694Val
NC_000016.9:g.3293407T>C
O15553:p.Met694Val

Protein change:

M694V; MET694VAL

Links:

UniProtKB: O15553#VAR_009062; OMIM: 608107.0001; dbSNP: rs61752717

NCBI 1000 Genomes Browser:

rs61752717

Molecular consequence:

NM_001198536.1:c.*284A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.2:c.2080A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Identifiers:: MedGen: CN517202

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279058	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 6, 2018)	germline	clinical testing	Citation Link,
SCV000281543	Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 24, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000331542	EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Aug 19, 2016)	germline	clinical testing	Citation Link,
SCV000604181	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jun 12, 2017)	germline	clinical testing	Citation Link

Help

Summary from all submissions

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000279058.9

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

Description

M694V is the most common FMF-associated pathogenic variant. In a series of 90 patients of different ethnic groups, M694V accounted for more than 30% of the MEFV pathogenic variants identified (Aksentijevich et al., 1999). M694V has also been published in association with FMF in additional individuals (The International FMF Consortium, 1997). The variant is observed in 56/126712 (0.044%) alleles in individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). While this substitution occurs at a position in the B30.2/SPRY domain that is not conserved, functional studies have shown that M694V has a damaging effect on the function of the MEFV protein (Sugiyama et al., 2014). Missense variants in the same residue (M694I/K) and in a nearby residue (K695R/M) have been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.

#	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, SCV000281543.1

#	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	0.000561	not provided	not provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000331542.4

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604181.2

#	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.2080A>G;p.Met694Val variant (rs61752717) has been published as a common familial Mediterranean fever (FMF) pathogenic variant (The International FMF Consortium 1997, Touitou 2001). Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2538), and is seen in the general population at an overall frequency of 0.03% (74/277222 including 1 homozygote) in the Genome Aggregation Database. Additionally, another variant at this codon (Met694Ile) has been reported in individuals with FMF and is considered pathogenic (Sugiyama 2014). Based on the above information, this variant is considered pathogenic. References: The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. 1997 Cell. 90:797-807. Sugiyama R et al. Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations. Mol Biol Rep. 2014 Jan;41(1):545-53. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):478-483.

#	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: Jan 26, 2020

ClinVar

Relating variation to medicine