16-3243447-C-T

Position:

chr16-3243447-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PS1PM1PM2PM5PP5_Very_StrongBP4

The NM_000243.3(MEFV):c.2040G>A(p.Met680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M680L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: -0.167

Variant links:

Genes affected

MEFV (HGNC:6998): (MEFV innate immunity regulator, pyrin) This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]

MEFV links:

MEFV (HGNC:):

MEFV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PS1

Transcript NM_000243.3 (MEFV) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3243449-T-G is described in Lovd as [Pathogenic].

PP5

Variant 16-3243447-C-T is Pathogenic according to our data. Variant chr16-3243447-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243447-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2989875). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.2040G>A	p.Met680Ile	missense_variant	10/10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 linkuse as main transcript	c.*244G>A		3_prime_UTR_variant	9/9		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.2040G>A	p.Met680Ile	missense_variant	10/10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2019	Variant summary: MEFV c.2040G>A (p.Met680Ile) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes (gnomAD). c.2040G>A has been reported in the literature in multiple individuals affected with Familial Mediterranean Fever (e.g. Akin_2010, Aksentijevich_1999). A different variant causing the same amino acid change (i.e. c.2040G>C, p.Met680Ile) is considered one of the most frequently observed MEFV mutations. Collectively, M680I without specifying nucleotide change, has been reported in multiple individuals affected with Familial Mediterranean Fever (e.g. Kriegshauser_2018, Yilmaz_2009). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Furthermore, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of pathogenic for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 680 of the MEFV protein (p.Met680Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 9288758, 10090880, 11977178, 21623663, 23907647, 23973724, 29080837). ClinVar contains an entry for this variant (Variation ID: 2550). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MEFV function (PMID: 21600797). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The c.2040G>A (p.Met680Ile) variant in MEFV has been reported, in the homozygous and compound heterozygous state, in numerous individuals with familial Mediterranean fever (FMF) (selected publications Aksentijevich 1999 PMID: 10090880, Sahin 2008 PMID: 18307385, Sabbagh 2008 PMID: 17566872, Jarjour 2010 PMID: 19253030, Akin 2010 PMID: 19449169). It has been reported in ClinVar (Variation ID 2550) and was identified in 2/68036 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Another variant at the same nucleotide position (c.2040G>C) resulting in the same amino acid change is a well-established pathogenic variant (Variation ID 36507). The p.Met680Ile aminoacid change (with cDNA change not specified) has also been reported in numerous additional individuals with FMF. In vitro functional studies support an impact to the protein function as this variant results in decreased binding of caspase-1 compared to wild-type (Chae 2006 PMID: 16785446). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS1, PS3_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 10, 2022	The MEFV c.2040G>A (p.Met680Ile) missense variant results in the substitution of methionine at amino acid position 680 with isoleucine. The c.2040G>A variant has been reported in at least four studies in which it is found in a total of eight probands with familial Mediterranean fever (FMF) including in one in a homozygous state, in five in a compound heterozygous state and in two in a heterozygous state (Aksentijevich et al. 1999; Sahin et al. 2008; Sabbagh et al. 2008; Jarjour et al. 2010). The c.2040G>A variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000029 in the European (non-Finnish) population (version 3.1.2). Another variant at the same nucleotide position (c.2040G>C) that results in the same amino acid change has been frequently reported in the literature as pathogenic for FMF. The p.Met680Ile variant has been reported in additional studies in which the cDNA change is not been specified. In at least 13 studies, the p.Met680Ile variant has been found in a homozygous state in at least 81 probands with FMF, in a compound heterozygous state in at least 159 probands with FMF, in a heterozygous state in at least 88 individuals with FMF and in nine of 431 controls (Cazeneuve et al. 1999; Shinawi et al. 2000; Akar et al. 2000; Yilmaz et al. 2001; Gershoni-Baruch et al. 2002; Etem et al. 2010; Talaat et al. 2012; Ocak et al. 2013; Moradian et al. 2014; Salehzadeh et al. 2015a; Salehzadeh et al. 2015b; Kilic et al. 2015; Salah et al. 2016). Functional studies demonstrate that the c.2040G>A variant results in decreased binding of caspase-1 compared to wild-type (Chae et al. 2006). Based on the available evidence, the c.2040G>A (p.Met680Ile) variant is classified as pathogenic for familial Mediterranean fever. -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002550). Different missense changes at the same codon (p.Met680Leu, p.Met680Val) have been reported to be associated with MEFV related disorder (PMID: 10842288, 28302131). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 15, 2019	- -

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2020	- -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MEFV: PM3:Very Strong, PS1, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 19, 2024	- -

Familial Mediterranean fever, autosomal dominant

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jul 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Aug 04, 2023	This variant has been observed in individuals with familial Mediterranean fever in heterozygous/compound heterozygous/homozygous state [PMID: 9288758, 10090880, 11977178, 21623663, 23907647, 23973724, 29080837]. Functional studies demonstrate that the variant results in decreased binding of caspase-1 compared to wild-type [PMID: 16785446]. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jun 07, 2020	- -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 25, 2022

- -

MEFV-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The MEFV c.2040G>A variant is predicted to result in the amino acid substitution p.Met680Ile. This variant, in the compound heterozygous or homozygous state, has been identified in patients with familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Bagheri and Rad. 2017. PubMed ID: 29218063). In addition, this variant has also been associated with Behcet’s disease (Wu et al. 2015. PubMed ID: 26176758). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.00023

BayesDel_noAF

Benign

-0.24

CADD

Benign

0.74

DANN

Benign

0.59

DEOGEN2

Benign

0.29

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.33

T;T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.60

N;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.13

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.36

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.30

MutPred

0.82

Gain of catalytic residue at M680 (P = 0.0329);.;.;

MVP

0.54

MPC

0.13

ClinPred

0.80

GERP RS

-3.3

Varity_R

0.23

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over