NM_000243.3(MEFV):c.2177T>C (p.Val726Ala) AND not provided

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

Germline classification:: Pathogenic/Likely 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:: RCV000220654.59

Allele description

NM_000243.3(MEFV):c.2177T>C (p.Val726Ala)

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.2177T>C (p.Val726Ala)

HGVS:

NC_000016.10:g.3243310A>G
NG_007871.1:g.18318T>C
NM_000243.3:c.2177T>CMANE SELECT
NM_001198536.2:c.*381T>C
NP_000234.1:p.Val726Ala
NP_000234.1:p.Val726Ala
LRG_190t1:c.2177T>C
LRG_190:g.18318T>C
LRG_190p1:p.Val726Ala
NC_000016.9:g.3293310A>G
NM_000243.2:c.2177T>C
O15553:p.Val726Ala
c.2177T>C (p.Val726Ala)

Protein change:

V726A; VAL726ALA

Links:

UniProtKB: O15553#VAR_009065; OMIM: 608107.0003; dbSNP: rs28940579

NCBI 1000 Genomes Browser:

rs28940579

Molecular consequence:

NM_001198536.2:c.*381T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.2177T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

175

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
SCV000224799	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Feb 15, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000279062	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 3, 2021)	germline	clinical testing	Citation Link,
SCV000281312	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]
SCV000604172	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 29, 2023)	germline	clinical testing	Citation Link,
SCV001150750	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,
SCV001449579	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001714542	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33440462, 25741868
SCV001744379	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001932036	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
SCV001959385	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
SCV001969445	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
SCV002022780	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242670	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	149	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	26	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient.

Camus D, Shinar Y, Aamar S, Langevitz P, Ben-Zvi I, Livneh A, Lidar M.

Clin Genet. 2012 Sep;82(3):288-91. doi: 10.1111/j.1399-0004.2011.01785.x. Epub 2011 Oct 14.

PubMed [citation]

PMID:: 21995303

The genomic landscape of pediatric rheumatology disorders in the Middle East.

Fathalla BM, Alsarhan A, Afzal S, El Naofal M, Abou Tayoun A.

Hum Mutat. 2021 Apr;42(4):e1-e14. doi: 10.1002/humu.24165. Epub 2021 Feb 7.

PubMed [citation]

PMID:: 33440462

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000224799.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	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		8	not provided	not provided	not provided

From GeneDx, SCV000279062.12

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

Description

In a series of 90 patients of different ethnic groups, V726A accounted for more than 20% of the MEFV pathogenic variants identified (Aksentijevich et al., 1999); Multiple published functional and FMF-knock-in mice studies demonstrate that this variant decreases protein binding activity (Chae et al., 2006) and shows decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, leading to constitutive activation of the pyrin inflammosome (Park YH et al., 2016); homozygosity for this MEFV variant in knock-in mice produced the most severe inflammation from all tested MEFV variants (Park YH 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: 28943464, 29080837, 19480334, 11781702, 29393966, 29707173, 29260407, 29326099, 30609409, 28828621, 22975760, 22532615, 22783597, 10090880, 23907647, 9288758, 21995303, 25333069, 23588594, 20669279, 20437121, 20483145, 10879615, 27994174, 27057533, 26400644, 26361084, 27538774, 28483595, 26360812, 18318646, 17408446, 28573371, 29431110, 30826945, 14615741, 11175300, 29543225, 31376265, 30783801, 32199921, 31447099, 32601469, 31589614, 33440462, 11977178, 33144682, 32888943, 10842289, 10852276, 32441320, 10662876, 16785446, 27270401, 19302049, 34549050)

#	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, SCV000281312.1

#	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	0.001794	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604172.10

#	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.2177T>C; p.Val726Ala variant (rs28940579) has been published in the literature in individuals with familial Mediterranean fever, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and multiple sclerosis with or without another pathogenic variant (Camus 2012, Comack 2013, Cosan 2010, Shinar 2012, Unal 2010). The variant is listed in the ClinVar database (Variation ID: 2540), and is observed in the general population at an overall frequency of 0.19% (561/282870 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. Pathogenic MEFV variants are causative for familial Mediterranean fever (MIM: 608107). References: Camus D et al. 'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient. Clin Genet. 2012 82(3):288-91. PMID: 21995303. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 172(8):1061-7. PMID: 23588594. Cosan F et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 2010 62(11):3232-6. PMID: 20669279. Shinar Y et al. Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus. Lupus. 2012 21(9):993-8. PMID: 22532615. Unal A et al. Evaluation of common mutations in the Mediterranean fever gene in Multiple Sclerosis patients: is it a susceptibility gene? J Neurol Sci. 2010 294(1-2):38-42. PMID: 20483145.

#	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, SCV001150750.19

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	81	not provided	not provided	clinical testing	not provided

Description

MEFV: PM3:Very Strong, PM2:Supporting, PP1, 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		81	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449579.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	68	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		68	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714542.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	PubMed (2)

Description

PM3, 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		18	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744379.3

#	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, SCV001932036.1

#	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, SCV001959385.1

#	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, SCV001969445.1

#	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, SCV002022780.3

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004242670.1

#	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: May 7, 2024

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