rs104895085
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000219596.6(MEFV):c.1958G>A(p.Arg653His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,848 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. R653C) has been classified as Likely benign.
Frequency
Consequence
ENST00000219596.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEFV | NM_000243.3 | c.1958G>A | p.Arg653His | missense_variant | 10/10 | ENST00000219596.6 | NP_000234.1 | |
MEFV | NM_001198536.2 | c.*162G>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 | c.1958G>A | p.Arg653His | missense_variant | 10/10 | 1 | NM_000243.3 | ENSP00000219596 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251200Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135764
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461590Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727066
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74438
ClinVar
Submissions by phenotype
Familial Mediterranean fever Pathogenic:5Uncertain:1Other:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 15, 2019 | - - |
Uncertain significance, flagged submission | clinical testing | Mendelics | May 28, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Jun 08, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 23, 2017 | 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. - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2001 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2016 | The R653H pathogenic variant in the MEFV that has been previously reported in association with Familial Mediterranean Fever (FMF) (Schaner et al., 2001; Timmann et al., 2001; Booty et al., 2009; Lazarin et al., 2013). It has also been observed in patients with juvenile idiopathic arthritis (Comak et al., 2013). The R653 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R653H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, a missense variant in a nearby residue (E656A) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 18, 2021 | The MEFV c.1958G>A; p.Arg653His variant (rs104895085) has been described in the heterozygous state in several individuals with a clinical diagnosis of familial Mediterranean fever and at least once in the compound heterozygous state in an individual with an additional pathogenic variant (Berdeli 2011, Botty 2009, Comak 2013, Jeske 2013, Oztuzcu 2014, Schaner 2001, Shinar 2007, Timmann 2001). The variant is reported in the ClinVar database (Variation ID: 2553) and is listed in the general population with an overall allele frequency of 0.0035% (10/282,580 alleles) in the Genome Aggregation Database. The arginine at codon 653 occurs in the SPRY domain, is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). However, most pathogenic MEFV variants occur in the SPRY domain (Manukyan 2016). Based on available information, this variant is classified as likely 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. Booty MG et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009 Jun;60(6):1851-61. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Jeske M et al. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. Klin Padiatr. 2013 Nov;225(6):325-30 Manukyan G and Aminov R Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever. Front. Microbiol. 2016 7:456. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. Schaner P et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet. 2001 Mar;27(3):318-21. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. Timmann C et al. Two novel mutations R653H and E230K in the Mediterranean fever gene associated with disease. Mutat Res. 2001 Aug 8;479(1-2):235-9. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 12, 2019 | - - |
Familial Mediterranean fever, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at