Submissions for variant NM_000243.3(MEFV):c.1459G>C (p.Val487Leu)

gnomAD frequency: 0.00207  dbSNP: rs104895100

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001712195	SCV000513592	likely benign	not provided	2020-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV000531412	SCV000629022	likely benign	Familial Mediterranean fever	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439116	SCV001437218	uncertain significance	not specified	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1459G>C (p.Val487Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 282892 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00077 vs 0.022), allowing no conclusion about variant significance. c.1459G>C has been reported in the literature in an individual (heterozygous) with clinically suspected Familial Mediterranean Fever (Gumus_2018). In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported classification and status of this variant as Unsolved (Van Gijn_2018). Recently however, Accetturo et al proposed a classification of likely benign (Accetturo _2019) based on a variant metapredictor tool REVEL (Rare Exome Variant Ensemble Learner) for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263676	SCV002543707	likely benign	Autoinflammatory syndrome	2019-11-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV003150813	SCV003839079	uncertain significance	Familial Mediterranean fever, autosomal dominant	2023-02-27	criteria provided, single submitter	clinical testing	This MEFV missense variant has been reported in an individual suspected to have familial Mediterranean fever. The variant (rs104895100) is present in a large population dataset (gnomAD v3.1.2: 339/152196 total alleles; 0.223%; 3 homozygotes), and has been reported in ClinVar2 (Variation ID 378132). Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The valine residue at this position is evolutionarily conserved across very few of the species assessed, and most of the species have leucine at this position. We consider the clinical significance of c.1459G>C; p.Val487Leu in MEFV to be uncertain at this time.
Johns Hopkins Genomics, Johns Hopkins University	RCV000531412	SCV003839090	uncertain significance	Familial Mediterranean fever	2023-02-27	criteria provided, single submitter	clinical testing	This MEFV missense variant has been reported in an individual suspected to have familial Mediterranean fever. The variant (rs104895100) is present in a large population dataset (gnomAD v3.1.2: 339/152196 total alleles; 0.223%; 3 homozygotes), and has been reported in ClinVar2 (Variation ID 378132). Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The valine residue at this position is evolutionarily conserved across very few of the species assessed, and most of the species have leucine at this position. We consider the clinical significance of c.1459G>C; p.Val487Leu in MEFV to be uncertain at this time.
Mayo Clinic Laboratories, Mayo Clinic	RCV001712195	SCV004227511	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	BP4
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001712195	SCV001978239	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001712195	SCV001980289	likely benign	not provided		no assertion criteria provided	clinical testing