VCV000036497.34 - ClinVar

NM_000243.3(MEFV):c.1016C>T (p.Ser339Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000243.3(MEFV):c.1016C>T (p.Ser339Phe)

Variation ID: 36497 Accession: VCV000036497.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3249675 (GRCh38) [ NCBI UCSC ] 16: 3299675 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 6, 2014	Oct 8, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000243.3:c.1016C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000234.1:p.Ser339Phe	missense
NM_001198536.2:c.383C>T	NP_001185465.2:p.Ser128Phe	missense
NC_000016.10:g.3249675G>A
NC_000016.9:g.3299675G>A
NG_007871.1:g.11953C>T
LRG_190:g.11953C>T
LRG_190t1:c.1016C>T	LRG_190p1:p.Ser339Phe

... more HGVS ... less HGVS

Protein change

S339F, S128F

Other names

Canonical SPDI

NC_000016.10:3249674:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00019

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00014

1000 Genomes Project 30x 0.00016

The Genome Aggregation Database (gnomAD) 0.00016

Exome Aggregation Consortium (ExAC) 0.00019

Links

ClinGen: CA280241 dbSNP: rs104895157 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MEFV		No evidence available	No evidence available	GRCh38 GRCh37	957	1258

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial Mediterranean fever	Uncertain significance (6)	criteria provided, multiple submitters, no conflicts	Oct 25, 2022	RCV000030169.15
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jan 26, 2024	RCV000366739.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 15, 2019	RCV001001441.8
Autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2018	RCV002262577.3
Familial Mediterranean fever, autosomal dominant	Uncertain significance (1)	criteria provided, single submitter	Mar 27, 2024	RCV003466877.3
MEFV-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 18, 2024	RCV004739311.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194409.3 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Feb 15, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158679.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The MEFV c.1016C>T; p.Ser339Phe (rs104895157) is reported in the Infevers database in an individual without a described phenotype (see link below). The variant is reported … (more) The MEFV c.1016C>T; p.Ser339Phe (rs104895157) is reported in the Infevers database in an individual without a described phenotype (see link below). The variant is reported in the ClinVar database (Variation ID: 36497) and in the general population with an overall allele frequency of 0.02% (50/279412 alleles) in the Genome Aggregation Database. The serine at this position is moderately conserved and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Link to Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 (less)
Uncertain significance (Jun 14, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279958.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 22580583‚ 26247045‚ 28421071‚ 22903357 Comment: 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, … (more) 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. (less)
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001805999.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021	Sex: mixed
Uncertain significance (Jul 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002543684.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Feb 09, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329420.7 First in ClinVar: Dec 06, 2016 Last updated: Jul 24, 2021	Comment: Reported in a patient with periodic fever in published literature (Federici et al., 2012); In silico analysis supports that this missense variant has a deleterious … (more) Reported in a patient with periodic fever in published literature (Federici et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22580583, 28421071, 30476289, 26247045) (less)
Uncertain significance (Oct 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000940571.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 21413889‚ 22580583‚ 22903357‚ 31989427 Comment: This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 339 of the MEFV protein (p.Ser339Phe). … (more) This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 339 of the MEFV protein (p.Ser339Phe). This variant is present in population databases (rs104895157, gnomAD 0.06%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 21413889, 22580583, 22903357, 31989427). ClinVar contains an entry for this variant (Variation ID: 36497). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less)
Uncertain significance (Jan 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449584.2 First in ClinVar: Dec 11, 2020 Last updated: Feb 04, 2024	Number of individuals with the variant: 1
Uncertain significance (Oct 02, 2015)	no assertion criteria provided Method: clinical testing	Familial Mediterranean Fever Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052827.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 06, 2014
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001452082.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927517.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953208.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (Jul 18, 2024)	no assertion criteria provided Method: clinical testing	MEFV-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005344956.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MEFV c.1016C>T variant is predicted to result in the amino acid substitution p.Ser339Phe. This variant has been reported the heterozygous and compound heterozygous states … (more) The MEFV c.1016C>T variant is predicted to result in the amino acid substitution p.Ser339Phe. This variant has been reported the heterozygous and compound heterozygous states in multiple individuals with familial Mediterranean fever (Berdeli et al. 2011. PubMed ID: 21413889; Balta et al. 2020. PubMed ID: 31989427; Lainka et al. 2012. PubMed ID: 22903357; Federici et al. 2012. PubMed ID: 22580583). This variant is reported in 0.049% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (-)	no classification provided Method: not provided	Familial Mediterranean fever Affected status: not provided Allele origin: unknown	Unité médicale des maladies autoinflammatoires, CHRU Montpellier Accession: SCV000115765.1 First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014
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Comment:

The MEFV c.1016C>T; p.Ser339Phe (rs104895157) is reported in the Infevers database in an individual without a described phenotype (see link below). The variant is reported in the ClinVar database (Variation ID: 36497) and in the general population with an overall allele frequency of 0.02% (50/279412 alleles) in the Genome Aggregation Database. The serine at this position is moderately conserved and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Link to Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1

Comment:

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.

Comment:

Reported in a patient with periodic fever in published literature (Federici et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22580583, 28421071, 30476289, 26247045)

Comment:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 339 of the MEFV protein (p.Ser339Phe). This variant is present in population databases (rs104895157, gnomAD 0.06%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 21413889, 22580583, 22903357, 31989427). ClinVar contains an entry for this variant (Variation ID: 36497). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

The MEFV c.1016C>T variant is predicted to result in the amino acid substitution p.Ser339Phe. This variant has been reported the heterozygous and compound heterozygous states in multiple individuals with familial Mediterranean fever (Berdeli et al. 2011. PubMed ID: 21413889; Balta et al. 2020. PubMed ID: 31989427; Lainka et al. 2012. PubMed ID: 22903357; Federici et al. 2012. PubMed ID: 22580583). This variant is reported in 0.049% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A comprehensive molecular analysis and genotype-phenotype correlation in patients with familial mediterranean fever.	Balta B	Molecular biology reports	2020	PMID: 31989427
Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.	Martorana D	Frontiers in immunology	2017	PMID: 28421071
Global epidemiology of Familial Mediterranean fever mutations using population exome sequences.	Fujikura K	Molecular genetics & genomic medicine	2015	PMID: 26247045
Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population.	Lainka E	European journal of pediatrics	2012	PMID: 22903357
Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population.	Federici S	Annals of the rheumatic diseases	2012	PMID: 22580583
Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey?	Berdeli A	Genetic testing and molecular biomarkers	2011	PMID: 21413889

Text-mined citations for rs104895157 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000243.3(MEFV):c.1016C>T (p.Ser339Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104895157 ...