NM_000243.3(MEFV):c.2040G>A (p.Met680Ile) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Apr 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:: RCV000216518.49

Allele description [Variation Report for NM_000243.3(MEFV):c.2040G>A (p.Met680Ile)]

NM_000243.3(MEFV):c.2040G>A (p.Met680Ile)

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.2040G>A (p.Met680Ile)

Other names:

MEFV, MET680ILE, 2040G-A; M680I

HGVS:

NC_000016.10:g.3243447C>T
NG_007871.1:g.18181G>A
NM_000243.3:c.2040G>AMANE SELECT
NM_001198536.2:c.*244G>A
NP_000234.1:p.Met680Ile
NP_000234.1:p.Met680Ile
LRG_190t1:c.2040G>A
LRG_190:g.18181G>A
LRG_190p1:p.Met680Ile
NC_000016.9:g.3293447C>T
NM_000243.2:c.2040G>A
O15553:p.Met680Ile
c.2040G>A (p.Met680Ile)

Protein change:

MET680ILE

Links:

UniProtKB: O15553#VAR_028343; OMIM: 608107.0013; dbSNP: rs28940580

NCBI 1000 Genomes Browser:

rs28940580

Molecular consequence:

NM_001198536.2:c.*244G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.2040G>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
SCV000279055	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 26, 2023)	germline	clinical testing	Citation Link,
SCV000604195	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (May 8, 2023)	germline	clinical testing	Citation Link,
SCV001134278	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Feb 20, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10090880, 22975760, 23907647, 11977178, 29080837, 21600797, 15951859, 26467025
SCV001245672	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link,
SCV001450258	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 2, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001550238	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV002017260	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 22, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002818286	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005198752	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 19, 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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.

Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL.

Am J Hum Genet. 1999 Apr;64(4):949-62.

PubMed [citation]

PMID:: 10090880
PMCID:: PMC1377819

An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.

Lazarin GA, Haque IS, Nazareth S, Iori K, Patterson AS, Jacobson JL, Marshall JR, Seltzer WK, Patrizio P, Evans EA, Srinivasan BS.

Genet Med. 2013 Mar;15(3):178-86. doi: 10.1038/gim.2012.114. Epub 2012 Sep 13.

PubMed [citation]

PMID:: 22975760
PMCID:: PMC3908551

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000279055.10

#	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 a reduced binding activity of the protein (Chae et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28289585, 23907647, 22975760, 10090880, 29543225, 32199921, 34426522, 32853466, 33440462, 33733382, 16785446, 19302049)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604195.4

#	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.2040G>A; p.Met680Ile variant (rs28940580) is reported in the literature in families affected with familial Mediterranean fever (FMF) (Moradian 2014, Procopio 2018), and segregates with disease when in-trans with another pathogenic variant (Aksentijevich 1999). This variant is also reported in ClinVar (Variation ID: 2550). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon resulting in the same amino acid alteration (c.2040G>C; p.Met680Ile) is a common pathogenic variant in FMF (Moradian 2014, Procopio 2018). Based on available information, this variant is considered to be pathogenic. References: Aksentijevich I et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999; 64(4):949-62. PMID: 10090880. Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014 Mar;16(3):258-63. PMID: 23907647. Procopio V et al. Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance? Gene. 2018 Jan 30;641:279-286. PMID: 29080837.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134278.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a tolerated effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

#	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, SCV001245672.25

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

Description

MEFV: PM3:Very Strong, PS1, 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		6	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450258.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	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		4	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550238.1

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

Description

The MEFV p.Met680Ile (c.2040G>A) variant was identified in 1 of 548 proband chromosomes (frequency: 0.0018) from individuals with Familial Mediterranean fever (FMF) (Aksentijevich_1999_PMID:10090880). The variant was also identified in dbSNP (ID: rs28940580), LOVD 3.0 and ClinVar (classified as pathogenic for FMF by GeneDx, ARUP Laboratories, Integrated Genetics, Invitae and Illumina). The variant was identified in control databases in 2 of 251474 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 2 of 113758 chromosomes (freq: 0.000018), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. Another variant in the MEFV gene, c.2040G>C, causes the same M680I missense change, and is a common variant associated with FMF (ClinVar ID: 36507). The M680I change was identified in 48/514 Turkish patients with FMF (freq=0.048; 20 heterozygotes, 27 compound heterozygotes, 1 homozygote), however the cDNA change causing this missense change (c.2040G>A or c.2040G>C) was not reported (Cekin_2017_PMID: 28483595). Although four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, the p.Met680 residue is conserved across mammals and other organisms. Further, functional studies of the M680I variant have demonstrated abnormal pyrin protein function (encoded by MEFV) as well as an FMF phenotype in M680I knock-in mice (Chae_2006_PMID: 16785446; Chae_2011_PMID: 21600797). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

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

From Revvity Omics, Revvity, SCV002017260.3

#	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 Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV002818286.1

#	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198752.1

#	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

Relating variation to medicine