Submissions for variant NM_000243.3(MEFV):c.329T>C (p.Leu110Pro)

gnomAD frequency: 0.00217  dbSNP: rs11466018

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175565	SCV000227074	benign	not specified	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000588731	SCV000279024	benign	not provided	2019-07-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in both the heterozygous and homozygous states in unaffected individuals and in individuals with familial Mediterranean fever (Kim et al., 2006; Tomiyama et al., 2008); This variant is associated with the following publications: (PMID: 24965843, 17329916, 22989844, 23166428, 24797171, 24598070, 10854105, 24929125, 20041150, 25073670, 22534884, 26332735, 29017770, 28482392, 29178647, 26537665, 19967574, 18328141, 25261100, 29642170, 26457478, 29526930, 29151129, 24661635, 32199921, 32735870)
Invitae	RCV001083220	SCV000629042	likely benign	Familial Mediterranean fever	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000175565	SCV000696068	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.329T>C (p.Leu110Pro) 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 0.0066 in 247780 control chromosomes, predominantly at a frequency of 0.084 within the East Asian subpopulation in the gnomAD database, including 61 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever phenotype (0.022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, the variant c.329T>C has also been commonly reported in FMF patients, primarily in the same allele (in cis) with p.E148Q, both in heterozygote and homozygote phases. In addition, multiple publications show lack of cosegregation for the variant and disease (Oshima_2010, Berdeli_2011, and Kim_2007). In Japanese population, the variant's allele frequency is higher in patients than in controls. Case-control studies in Japanese population indicate this variant may associate with increased risk of FMF (OR= 1.78, Migita_2016; OR=4.81, Tsuchiya-Suzuki_2009). Larger case-control studies are needed to validate these findings. At least one functional study demonstrated no damaging effect of this variant (Honda_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of uncertain significance for the variant (Van Gijn_2018). Based on the data available at this time, it is unknown whether this variant represents a low penetrance mild common pathogenic variant, modifier, or a risk allele. Therefore, this variant was classified as uncertain significance, until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588731	SCV000884107	likely benign	not provided	2022-02-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083220	SCV001277846	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000588731	SCV001450092	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001083220	SCV001653449	uncertain significance	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262770	SCV002543754	benign	Autoinflammatory syndrome	2021-05-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001083220	SCV001462431	uncertain significance	Familial Mediterranean fever	2020-01-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588731	SCV001977937	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588731	SCV001979697	uncertain significance	not provided		no assertion criteria provided	clinical testing