NM_000243.3(MEFV):c.1958G>A (p.Arg653His) AND Familial Mediterranean fever

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Sep 10, 2025
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:: RCV000002662.28

Allele description [Variation Report for NM_000243.3(MEFV):c.1958G>A (p.Arg653His)]

NM_000243.3(MEFV):c.1958G>A (p.Arg653His)

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.1958G>A (p.Arg653His)

Other names:

R653H

HGVS:

NC_000016.10:g.3243529C>T
NG_007871.1:g.18099G>A
NM_000243.3:c.1958G>AMANE SELECT
NM_001198536.2:c.*162G>A
NP_000234.1:p.Arg653His
NP_000234.1:p.Arg653His
LRG_190t1:c.1958G>A
LRG_190:g.18099G>A
LRG_190p1:p.Arg653His
NC_000016.9:g.3293529C>T
NM_000243.1:c.1958G>A
NM_000243.2:c.1958G>A
O15553:p.Arg653His

Protein change:

ARG653HIS

Links:

UniProtKB: O15553#VAR_016828; OMIM: 608107.0016; dbSNP: rs104895085

NCBI 1000 Genomes Browser:

rs104895085

Molecular consequence:

NM_001198536.2:c.*162G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.1958G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial Mediterranean fever (FMF)
Synonyms:: POLYSEROSITIS, FAMILIAL PAROXYSMAL; POLYSEROSITIS, RECURRENT; Periodic peritonitis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018088; MedGen: C0031069; Orphanet: 342; OMIM: 249100

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022820	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000115818	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV000484964	GeneReviews	no classification provided	not provided	germline	literature only
SCV000696058	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 23, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19479870, 21413889, 11470495, 24158885, 26620106 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001132429	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 15, 2019)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 21413889, 11470495, 15951859, 11242116, 17665427, 24469716, 24158885, 26620106, 16378925, 17938136, 23633568, 19479870
SCV001415945	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 30, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11470495, 16378925, 19479870, 21413889, 24469716, 29159471, 31989427, 28492532
SCV003930290	Intergen Genetics and Rare Diseases Diagnosis Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006553126	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 10, 2025)	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	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Genetic screening of familial Mediterranean fever mutations in the Palestinian population.

Ayesh SK, Nassar SM, Al-Sharef WA, Abu-Libdeh BY, Darwish HM.

Saudi Med J. 2005 May;26(5):732-7.

PubMed [citation]

PMID:: 15951859

Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states.

Schaner P, Richards N, Wadhwa A, Aksentijevich I, Kastner D, Tucker P, Gumucio D.

Nat Genet. 2001 Mar;27(3):318-21.

PubMed [citation]

PMID:: 11242116

See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000022820.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In the study of the evolution of pyrin in primates, Schaner et al. (2001) reported a 1958G-A transition in the MEFV gene that resulted in an arg653-to-his (R653H) change. They pointed out that the human wildtype amino acid, arginine, is seen only in gorilla, chimp, and human. All other species (except dwarf lemur) contain histidine at this position. Thus, histidine is most likely the ancestral amino acid, and the human disease mutation from arginine to histidine replicates this ancestral (and highly conserved) state. A similar kind of pattern was seen in the evolutionary history of other codons.

#	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	not provided	not provided	not provided

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000115818.1

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

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

From GeneReviews, SCV000484964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696058.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: The MEFV c.1958G>A (p.Arg653His) variant located in the SPRY domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 2/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 6/121204 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple publications have cited the variant in affected individuals in whom a second mutation not identified. Of note, this variant was reported in one affected individual who met the Tel-Hashomer criteria for a diagnosis of MEFV as a compound heterozygote along with p.M694V. The unaffected mother and brother were carriers for the variant of interest. In addition, Booty_2009 reports a clinically diagnosed FMF affected sib-pair that each carry only the variant of interest following a comprehensive search for a second mutation in the MEFV gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, although no in-vitro or in-vivo functional studies supporting a damaging outcome for this variant have been reported, the ascertained evidence has been weighted to classify this variant as Pathogenic.

#	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 Counsyl, SCV001132429.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

From Mendelics, SCV001139836.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001415945.4

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 653 of the MEFV protein (p.Arg653His). This variant is present in population databases (rs104895085, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 11470495, 16378925, 19479870, 21413889, 24469716, 29159471, 31989427; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2553). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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 Intergen Genetics and Rare Diseases Diagnosis Center, SCV003930290.1

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

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV006553126.1

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001139836	Mendelics	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001139836

Mendelics

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link

Last Updated: Dec 1, 2025

Relating variation to medicine