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

Germline classification:
Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:
Jan 27, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000002662.23

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000022820OMIM
no assertion criteria provided
Pathogenic
(Mar 1, 2001)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000115818Unité médicale des maladies autoinflammatoires, CHRU Montpellier
no classification provided
not providedunknownnot provided

SCV000484964GeneReviews
no classification provided
not providedgermlineliterature only

SCV000696058Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Feb 23, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001132429Counsyl
no assertion criteria provided
Likely pathogenic
(Mar 15, 2019)
unknownclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001139836Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Uncertain significance
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001415945Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Jan 27, 2024)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV003930290Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 8, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot provided1not providedliterature 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot provided1not providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000484964.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696058.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV001132429.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001139836.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001415945.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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; Invitae). 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). 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. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 23, 2024