Submissions for variant NM_000243.3(MEFV):c.688G>A (p.Glu230Lys)

gnomAD frequency: 0.00001  dbSNP: rs104895080

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213898	SCV000279040	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing	The E230K missense mutation in the MEFV gene has been reported previously in association with Familial Mediterranean Fever (FMF) (Touitou et al., 2001, Timmann et al., 2001; Ceylan et al., 2012). It was also published in association with multiple sclerosis in a patient with symptoms and positive family history of FMF (Blaschek et al., 2010). Per the 1000 Genomes Consortium, E230K was observed at a frequency of 1.74%, 3/172 alleles, in individuals of Bengali ancestry (McVean et al., 2012). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Counsyl	RCV000083789	SCV000677982	uncertain significance	Familial Mediterranean fever	2017-05-08	criteria provided, single submitter	clinical testing
Invitae	RCV000083789	SCV001019264	likely benign	Familial Mediterranean fever	2024-01-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000083789	SCV001139880	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000213898	SCV001150756	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MEFV: PM3:Strong, PM2:Supporting, BP4
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027835	SCV001190455	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2019-05-14	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. Computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000083789	SCV001274515	uncertain significance	Familial Mediterranean fever	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000083789	SCV001652748	uncertain significance	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262651	SCV002542301	uncertain significance	Autoinflammatory syndrome	2021-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265603	SCV002547916	uncertain significance	not specified	2023-03-17	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.688G>A (p.Glu230Lys) 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 0.00063 in 249694 control chromosomes, predominantly at a frequency of 0.0047 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00063 vs 0.022), allowing no conclusion about variant significance. c.688G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals reportedly meeting the clinical diagnostic criteria for Familial Mediterranean Fever (FMF) (example, Timmann_2001, Kallinich_2010, Berdelli_2011, Lainka_2012, Omenetti_2013, Gohar_2016, Arpaci_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as VUS (n=8) (Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224143	SCV003920200	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-03-30	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. Computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Neuberg Centre For Genomic Medicine, NCGM	RCV004546431	SCV005042639	uncertain significance	Familial Mediterranean fever, autosomal dominant		criteria provided, single submitter	clinical testing	The missense c.688G>A p.Glu230Lys variant in MEFV gene has been reported previously in compound heterozygous state in individuals affected with Familial Mediterranean fever FMF Timmann et al., 2001. This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glu at position 230 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu230Lys in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083789	SCV000115887	not provided	Familial Mediterranean fever		no assertion provided	not provided
Centogene AG - the Rare Disease Company	RCV000083789	SCV001424453	pathogenic	Familial Mediterranean fever		flagged submission	clinical testing