Submissions for variant NM_000243.3(MEFV):c.524C>A (p.Pro175His)

gnomAD frequency: 0.00001  dbSNP: rs104895126

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083779	SCV001212803	uncertain significance	Familial Mediterranean fever	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 175 of the MEFV protein (p.Pro175His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 97527). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV001588911	SCV001826962	uncertain significance	not provided	2020-07-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262647	SCV002542288	uncertain significance	Autoinflammatory syndrome	2019-04-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490736	SCV002793542	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2024-04-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000083779	SCV003802340	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126477	SCV003802341	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126478	SCV003802342	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237527	SCV005884145	uncertain significance	not specified	2024-12-10	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.524C>A (p.Pro175His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 1550910 control chromosomes in the gnomAD database (v4.1 dataset). This frequency is not higher than the maximum estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.524C>A in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 97527). Based on the evidence outlined above, the variant was classified as uncertain significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083779	SCV000115877	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083779	SCV002087452	uncertain significance	Familial Mediterranean fever	2020-09-24	no assertion criteria provided	clinical testing