NM_000243.3:c.501G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000243.3(MEFV):c.501G>C(p.Glu167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,571,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:7O:1

Conservation

PhyloP100: 0.300

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 16-3254567-C-G is Pathogenic according to our data. Variant chr16-3254567-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2543.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=7, not_provided=1}. Variant chr16-3254567-C-G is described in Lovd as [Likely_pathogenic]. Variant chr16-3254567-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.501G>C	p.Glu167Asp	missense_variant	Exon 2 of 10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 link	c.277+1744G>C		intron_variant	Intron 1 of 8		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.501G>C	p.Glu167Asp	missense_variant	Exon 2 of 10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152218

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

181710

Hom.:

AF XY:

0.0000397

AC XY:

AN XY:

100690

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:

0.0000919

Gnomad OTH exome

AF:

0.000206

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1419548

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

703922

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:

0.0000311

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

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:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000849

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Apr 02, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Occurs frequently with the F479L variant, usually proven to be on the same allele (in cis) and often considered a complex allele (PMID: 9668175, 19863562, 32199921, 22614345); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25393764, 11175300, 32199921, 19863562, 17489852, 22614345, 24469716, 15024744, 29178647, 10090880, 18609258, 25708585, 34426522, 35831068, Chirita2022[PrePrint], 34120219, Ahmed2022[Article], 33079202, 32921628, 36249512, 36223753, Altamimi2022[Preprint], Sav2022[Preprint], 33611656, 35110061, 26351556, Gungorer2022[Article], 21413889, 12180071, 19026119, 29047407, 33738724, 33733382, 26003477, 22661645, 10842288, 10737992, 10364520, 39581688, 39042260, 26247045, 36725780, 37773839, 29599418, 33165748, 39462592, 36966139, 9668175) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV: PM3:Very Strong, PM2, BP4 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.501G>C; p.Glu167Asp variant (rs104895079) is reported in the homozygous and compound heterozygous state in affected individuals (Ceylan 2012, Papa 2017, Ustek 2008) and is often found on the same chromosome as c.1437C>G; p.Phe479Leu (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015). However, the c.1437C>G; p.Phe479Leu variant was not detected in this individual. The.501G>C; p.Glu167Asp variant was described as likely pathogenic by a panel of experts (Van Gijn 2018) and is listed in the ClinVar database (Variation ID: 2543). The variant is described in the general population with an overall allele frequency of 0.005% (10/213,066 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.535). Due to the uncertainty regarding the pathogenicity of the p.Glu167Asp variant when found individually, the clinical significance of the p.Glu167Asp variant is uncertain at this time. References: 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. Bonyadi M et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet. 2009 Nov;76(5):477-80. Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. Mansour I et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet. 2001 Jan;9(1):51-5. 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 Papa R et al A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. Ustek D et al. MEFV gene 3'-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2008 Jul-Aug;26(4 Suppl 50):S72-6. [OR] The MEFV c.[501G>C;1437C>G]; p.[Glu167Asp;Phe479Leu] variant is a complex allele consisting of two changes on the same chromosome, p.Glu167Asp and p.Phe479Leu. Although p.Phe479Leu has been reported on its own, to the best of our knowledge p.Glu167Asp has only been reported as a complex allele with p.Phe479Leu. The complex variant has been published in the literature in both the homozygous and compound heterozygous state in individuals affected with familial Mediterranean fever (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015) and is one of the most common pathogenic MEFV variants in the Cypriot populations (Neocleous 2015). Based on available information, this variant is considered to be pathogenic. References: 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. Bonyadi M et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet. 2009 Nov;76(5):477-80. Mansour I et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet. 2001 Jan;9(1):51-5. 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 -

Jan 11, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever

Pathogenic:3Uncertain:2Other:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 167 of the MEFV protein (p.Glu167Asp). This variant is present in population databases (rs104895079, gnomAD 0.01%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Phe479Leu variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 12180071, 25708585, 25393764, 21413889, 26351556, 24469716, 29178647). In some of these individuals, an additional MEFV variant was not identified on the opposite allele, while in others, multiple additional MEFV variants were identified. Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 2543). ClinVar contains an entry for this variant (Variation ID: 2543). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial Mediterranean fever, autosomal dominant

Uncertain:2

Oct 24, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome

Pathogenic:1

Sep 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Apr 06, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEFV c.501G>C (p.Glu167Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 182315 control chromosomes (gnomAD, exomes dataset). c.501G>C (p.E167D) is often observed in the same chromosome (in cis) with c.1437C>G (p.Phe479Leu) forming a complex allele p.[E167D;F479L]. Nevertheless, E167D has also been reported in the literature as a variant in isolation in homozygous or compound heterozygous state, in a few individuals affected with Familial Mediterranean Fever (e.g. Ceylan_2012, Papa_2017, Ustek_2008, Bozgeyik_2020). These data indicate that the variant is likely to be associated with disease. In 2012, an international consortium of experts reached a consensus (as part of an agreed set of best practice guidelines) to test for 14 MEFV variants, nine of which were considered pathogenic (including E167D) and 5 of unknown significance (Shinar_2012). In addition, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) agreed in a consensus classification of (provisional) likely pathogenic for the variant (Van Gijn_2018). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments citing overlapping evidence utilized in the context of this evaluation (Pathogenic/Likely pathogenic, n=5; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.69

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.54

Sift

Uncertain

0.014

Sift4G

Benign

0.17

Polyphen

0.60

Vest4

0.31

MutPred

0.69

Loss of solvent accessibility (P = 0.0635);

MVP

0.85

MPC

0.29

ClinPred

0.10

GERP RS

2.0

Varity_R

0.14

gMVP

0.38

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