chr16-3243205-C-T

Position:

chr16-3243205-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000243.3(MEFV):c.2282G>A(p.Arg761His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R761C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31O:2

Conservation

PhyloP100: 0.399

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

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 chr16-3243206-G-A is described in Lovd as [Likely_pathogenic].

PP5

Variant 16-3243205-C-T is Pathogenic according to our data. Variant chr16-3243205-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243205-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3 linkuse as main transcript	c.2282G>A	p.Arg761His	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2 linkuse as main transcript	c.*486G>A		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 linkuse as main transcript	c.2282G>A	p.Arg761His	missense_variant	10/10	1	NM_000243.3	ENSP00000219596	P3	O15553-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251436

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00174

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000923

AC:

135

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000105

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000852

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:12Other:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Arg761His (NM_000243.2 c.2282G>A) variant in MEFV has been reported in over 20 heterozygous, 10 homozygous, and 50 compound heterozygous individuals with familial Mediterranean fever (FMF) (Bernot 1998 PMID: 9668175, Ece 2015 PMID: 24071932, Salehzadeh 2015 PMID: 25648235, Beheshtian 2016 PMID: 27659338). It has also been reported in ClinVar (Variation ID# 2549), as pathogenic. This variant has been identified in 0.2% (38/18870) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104895097). This frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Arg761His variant meets criteria to be classified as pathogenic for FMF in an autosomal recessive manner based upon its occurrence in affected individuals. ACMG/AMP criteria applied: PM3_VStrong, PP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The MEFV c.2282G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to His. 2/4 in-silico tools predict this variant to be deleterious. This variant was found in 28/121772 control chromosomes at a frequency of 0.0002299, which does not exceed maximal expected frequency of a pathogenic MEFV allele (0.0216506). In addition, this variant is considered pathogenic in the literature and has been identified in many FMF patients in homozygous and compound heterozygous state. Taken together, this variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000243.2(MEFV):c.2282G>A(R761H) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of MEFV mutation status is uncertain. Sources cited for classification include the following: PMID 19863562, 16378925 and 9668175. Classification of NM_000243.2(MEFV):c.2282G>A(R761H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 761 of the MEFV protein (p.Arg761His). This variant is present in population databases (rs104895097, gnomAD 0.2%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 9668175, 17566872, 21413889, 23031807, 23038988, 23907647, 25393764, 26351556, 27980538). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2549). 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 histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of available literature, the MEFV c.2282G>A (p.Arg761His) missense variant has been identified in 82 patients with familial Mediterranean fever, including in a homozygous state in seven patients, in a compound heterozygous state in 50 patients, and in a heterozygous state in 25 patients (Bernot A et al. 1998; Bonyadi M et al. 2009; Ece A et al. 2013; Neocleous et al. 2014; Salehzadeh et al. 2015). Moradian et al. (2014) found the p.Arg761His variant at a frequency of 3.46% in a population of 16,000 Armenian familial Mediterranean fever patients, while the frequency of the variant in the control group was 0.20%. The p.Arg761His variant was absent from 99 controls and is reported at a frequency of 0.00231 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg761His variant is classified as pathogenic for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 29, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The MEFV c.2282G>A; p.Arg761His variant (rs104895097) has been described in the homozygous, heterozygous, and compound heterozygous states in individuals affected with familial Mediterranean fever (FMF; Berdeli 2011, Bernot 1998, Moradian 2014, Neocleous 2015, Ong 2013). It is reported as pathogenic in ClinVar (Variation ID: 2549) and observed in the general population at an overall frequency of 0.02% (58/282,828 alleles) in the Genome Aggregation Database. The arginine at codon 761 is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.352). Additionally, another variant at this codon (c.2281C>A; p.Arg761His) has been described in multiple individuals affected with FMF and is considered pathogenic (Ozalkaya 2011). Based on available information, the p.Arg761His variant is considered pathogenic. REFERENCES Berdeli A et al. Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey? Genet Test Mol Biomarkers. 2011 Jul-Aug;15(7-8):475-82. Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. Moradian M 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. Neocleous V et al. Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Ann Hum Genet. 2015 Jan;79(1):20-7. Ong F et al. The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. Clin Genet. 2013 Jul;84(1):55-9. Ozalkaya E et al. Familial Mediterranean fever gene mutation frequencies and genotype-phenotype correlations in the Aegean region of Turkey. Rheumatol Int. 2011 Jun;31(6):779-84. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2019	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MEFV: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 28, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18496034, 22580583, 23844200, 22953644, 27980538, 28486679, 10090880, 9668175, 23588594, 22975760, 23907647, 18000697, 19934083, 24141617, 10364520, 25727825, 19479870, 18328141, 25232290, 25202401, 24592325, 19863562, 27621632, 25449140, 26351556, 26543317, 30609409, 29543225, 30476289, 31376265, 30783801, 28828621, 34426522, 31589614, 29080837, 27659338, 25648235, 25703702, 25615955, 25393764, 19302049) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 09, 2024	- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.2282G>A (p.R761H) alteration is located in exon 10 (coding exon 10) of the MEFV gene. This alteration results from a G to A substitution at nucleotide position 2282, causing the arginine (R) at amino acid position 761 to be replaced by a histidine (H)._x000D_ _x000D_ Based on the available evidence, the clinical significance of the MEFV c.2282G>A (p.R761H) alteration is uncertain for autosomal dominant familial Mediterranean fever (FMF); however, this variant is likely pathogenic for autosomal recessive FMF. Based on data from gnomAD, the A allele has an overall frequency of 0.02% (58/282,828) total alleles studied. The highest observed frequency was 0.19% (38/19,954) of East Asian alleles. This alteration has been reported homozygous or compound heterozygous with a second mutation in MEFV in multiple patients with autosomal recessive familial Mediterranean fever (FMF) (Bernot, 1998; Bonyadi, 2009; Ece, 2014; Salehzadeh, 2015). It has also been reported heterozygous in patients with a milder form of FMF (Moradian, 2010; Procopio, 2018). Of these cases, 25% were associated with fever (Procopio, 2018) This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Familial Mediterranean fever, autosomal dominant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 29, 2022

- -

MEFV-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2024

The MEFV c.2282G>A variant is predicted to result in the amino acid substitution p.Arg761His. This variant has previously been reported in the compound heterozygous state in individuals who presented with familial Mediterranean fever (FMF; see Bernot et al. 1998. PubMed ID: 9668175; Moradian et al. 2014. PubMed ID: 23907647; http://fmf.igh.cnrs.fr/ISSAID/infevers/). This variant is reported in 0.19% of alleles in individuals of East Asian descent in gnomAD and is classified as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2549/). We interpret this variant to be pathogenic. -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.19

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.26

T;T;T

M_CAP

Benign

0.0047

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

N;.;.

MutationTaster

Benign

1.2e-12

A;A;A;A

PrimateAI

Benign

0.25

PROVEAN

Benign

2.8

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.057

MutPred

0.82

Loss of sheet (P = 0.0817);.;.;

MVP

0.42

MPC

0.14

ClinPred

0.0047

GERP RS

1.3

Varity_R

0.14

gMVP

0.19

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