Submissions for variant NM_000243.3(MEFV):c.1043G>A (p.Arg348His)

gnomAD frequency: 0.00010  dbSNP: rs104895198

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000083679	SCV000396773	uncertain significance	Familial Mediterranean fever	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000755567	SCV000513590	likely benign	not provided	2019-11-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000417776	SCV000604191	uncertain significance	not specified	2018-11-08	criteria provided, single submitter	clinical testing	The MEFV c.1043G>A; p.Arg348His variant (rs104895198), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 97428). This variant is found in the general population with an overall allele frequency of 0.018% (50/279,346 alleles) in the Genome Aggregation Database. The arginine at codon 348 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg348His variant is uncertain at this time.
Invitae	RCV000083679	SCV000820726	uncertain significance	Familial Mediterranean fever	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 348 of the MEFV protein (p.Arg348His). This variant is present in population databases (rs104895198, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MEFV-related conditions. ClinVar contains an entry for this variant (Variation ID: 97428). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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 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.
CeGaT Center for Human Genetics Tuebingen	RCV000755567	SCV001150754	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262629	SCV002543685	uncertain significance	Autoinflammatory syndrome	2018-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417776	SCV003934372	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1043G>A (p.Arg348His) results in a non-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 0.00019 in 247954 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00019 vs 0.022), allowing no conclusion about variant significance. c.1043G>A has been reported in the literature in individuals affected with Autoinflammatory Disease (e.g. Kirnaz_2022, Kirino_2013). These reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23633568, 35358658). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083679	SCV000115766	not provided	Familial Mediterranean fever		no assertion provided	not provided