Submissions for variant NM_000243.3(MEFV):c.1795A>G (p.Asn599Asp)

gnomAD frequency: 0.00021  dbSNP: rs104895210

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218478	SCV000279053	uncertain significance	not provided	2016-03-03	criteria provided, single submitter	clinical testing	An abstract presented at the 7th Congress of the International Soceity of Systemic Auto-Inflammatory Diseases describes one FMF patient with N599D (Aladbe et al., 2013). The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. N599D is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000083716	SCV000943276	uncertain significance	Familial Mediterranean fever	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 599 of the MEFV protein (p.Asn599Asp). This variant is present in population databases (rs104895210, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 18409191, 21520333). ClinVar contains an entry for this variant (Variation ID: 97464). 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 aspartic acid 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262636	SCV002543724	uncertain significance	Autoinflammatory syndrome	2021-01-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505013	SCV002814659	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-03-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000083716	SCV003802027	likely benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126435	SCV003802028	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126436	SCV003802029	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083716	SCV000115808	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083716	SCV002087380	uncertain significance	Familial Mediterranean fever	2019-10-28	no assertion criteria provided	clinical testing