Variant summary: MEFV c.322A>C (p.Ser108Arg) 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 8.1e-06 in 247374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322A>C has been reported in the literature in individuals affected with Periodic Fever Syndrome (e.g. Gattorno_2009, Federici_2012) and familial Mediterranean fever (e.g. Medlej-Hashim_2005, Omenetti_2014, Ozen_2014, Papa_2017), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with another pathogenic variant have been reported (example, Omenetti_2014) and observed at our laboratory (MEFV c.2177T>C, p.Val726Ala), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Furthermore, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of uncertain significance for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_000243.3(MEFV):c.322A>C (p.Ser108Arg)
Germline
Classification
Help
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.
(15)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(11); Likely benign(2)
Uncertain significance(11); Likely benign(2)
15
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000243.3(MEFV):c.322A>C (p.Ser108Arg)
Variation ID: 97515 Accession: VCV000097515.53
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 3254746 (GRCh38) [ NCBI UCSC ] 16: 3304746 (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 Feb 20, 2014 Oct 20, 2024 Dec 22, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000243.3:c.322A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000234.1:p.Ser108Arg missense NM_001198536.2:c.277+1565A>C intron variant NC_000016.10:g.3254746T>G NC_000016.9:g.3304746T>G NG_007871.1:g.6882A>C LRG_190:g.6882A>C LRG_190t1:c.322A>C LRG_190p1:p.Ser108Arg O15553:p.Ser108Arg - Protein change
- S108R
- Other names
- -
- Canonical SPDI
- NC_000016.10:3254745:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
961 | 1262 | |
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. |
|---|---|---|---|---|
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 22, 2023 | RCV000083767.20 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2023 | RCV000586697.34 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 16, 2022 | RCV001000180.18 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 1, 2020 | RCV002262644.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 1, 2016 | RCV002321581.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 5, 2022 | RCV002477246.8 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 8, 2023 | RCV003126471.8 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 8, 2023 | RCV003126472.8 |
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
(Apr 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696067.3
First in ClinVar: Mar 17, 2018 Last updated: May 16, 2022 |
Comment:
Variant summary: MEFV c.322A>C (p.Ser108Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: MEFV c.322A>C (p.Ser108Arg) 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 8.1e-06 in 247374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322A>C has been reported in the literature in individuals affected with Periodic Fever Syndrome (e.g. Gattorno_2009, Federici_2012) and familial Mediterranean fever (e.g. Medlej-Hashim_2005, Omenetti_2014, Ozen_2014, Papa_2017), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with another pathogenic variant have been reported (example, Omenetti_2014) and observed at our laboratory (MEFV c.2177T>C, p.Val726Ala), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Furthermore, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of uncertain significance for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Mar 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543753.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139895.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Apr 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156672.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound … (more)
The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound heterozygous with the pathogenic V726A allele (Federici 2012, Gattorno 2009, Kilinc 2016, Medlej-Hashim 2005). This variant is classified as uncertain in ClinVar (Variation ID: 97515). It is only observed in two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on currently available information, it is uncertain whether this variant is benign or disease-associated. REFERENCES Federici S et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis. 2012 Dec;71(12):1961-5. Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Kilinc M et al. The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int. 2016 Jan;36(1):25-31. Medlej-Hashim M et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20. (less)
|
|
|
Uncertain significance
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318716.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000081). A missense variant is a common mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000081). A missense variant is a common mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MEFV related disorder (PMID:16378925). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Failure to thrive (present) , Meningitis (present) , Recurrent infections (present) , Recurrent pneumonia (present) , Venous thrombosis (present)
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003802419.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Likely benign
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003802420.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Likely benign
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Acute febrile neutrophilic dermatosis
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003802421.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Uncertain significance
(Apr 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002610276.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S108R variant (also known as c.322A>C), located in coding exon 2 of the MEFV gene, results from an A to C substitution at nucleotide … (more)
The p.S108R variant (also known as c.322A>C), located in coding exon 2 of the MEFV gene, results from an A to C substitution at nucleotide position 322. The serine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in two individuals with FMF; one individual also had the p.V726A pathogenic mutation and the second individual had two additional alterations in the MEFV gene. The phase of these alterations (whether in cis or trans) is not known (Medlej-Hashim M, Eur J Med Genet ; 48(4):412-20). This variant was previously reported in the SNPDatabase as rs104895103. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
|
|
|
Uncertain significance
(Apr 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Familial Mediterranean fever Acute febrile neutrophilic dermatosis
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000896547.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279023.12
First in ClinVar: May 29, 2016 Last updated: May 20, 2023 |
Comment:
Observed in the heterozygous state in patients with MEFV-related periodic fever syndromes, often in individuals also heterozygous for the p.(V726A) variant, but it is not … (more)
Observed in the heterozygous state in patients with MEFV-related periodic fever syndromes, often in individuals also heterozygous for the p.(V726A) variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Medlej-Hashim et al., 2005; Salehzadeh et al., 2014; Kilinc et al., 2016; Papa et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26215181, 25793047, 29047407, 23463692, 19786432, 22580583, 16378925, 33844039, El Hawary_2022) (less)
|
|
|
Uncertain significance
(Dec 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000817485.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 108 of the MEFV protein (p.Ser108Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 108 of the MEFV protein (p.Ser108Arg). This variant is present in population databases (rs104895103, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 16378925, 19786432, 29047407). ClinVar contains an entry for this variant (Variation ID: 97515). 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. (less)
|
|
|
Uncertain significance
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247642.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001457158.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
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: SCV000115863.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
|
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Comment:
Comment:
The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound heterozygous with the pathogenic V726A allele (Federici 2012, Gattorno 2009, Kilinc 2016, Medlej-Hashim 2005). This variant is classified as uncertain in ClinVar (Variation ID: 97515). It is only observed in two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on currently available information, it is uncertain whether this variant is benign or disease-associated. REFERENCES Federici S et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis. 2012 Dec;71(12):1961-5. Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Kilinc M et al. The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int. 2016 Jan;36(1):25-31. Medlej-Hashim M et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000081). A missense variant is a common mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MEFV related disorder (PMID:16378925). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
The p.S108R variant (also known as c.322A>C), located in coding exon 2 of the MEFV gene, results from an A to C substitution at nucleotide position 322. The serine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in two individuals with FMF; one individual also had the p.V726A pathogenic mutation and the second individual had two additional alterations in the MEFV gene. The phase of these alterations (whether in cis or trans) is not known (Medlej-Hashim M, Eur J Med Genet ; 48(4):412-20). This variant was previously reported in the SNPDatabase as rs104895103. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Comment:
Observed in the heterozygous state in patients with MEFV-related periodic fever syndromes, often in individuals also heterozygous for the p.(V726A) variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Medlej-Hashim et al., 2005; Salehzadeh et al., 2014; Kilinc et al., 2016; Papa et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26215181, 25793047, 29047407, 23463692, 19786432, 22580583, 16378925, 33844039, El Hawary_2022)
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 108 of the MEFV protein (p.Ser108Arg). This variant is present in population databases (rs104895103, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 16378925, 19786432, 29047407). ClinVar contains an entry for this variant (Variation ID: 97515). 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.
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:
Variant summary: MEFV c.322A>C (p.Ser108Arg) 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 8.1e-06 in 247374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322A>C has been reported in the literature in individuals affected with Periodic Fever Syndrome (e.g. Gattorno_2009, Federici_2012) and familial Mediterranean fever (e.g. Medlej-Hashim_2005, Omenetti_2014, Ozen_2014, Papa_2017), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with another pathogenic variant have been reported (example, Omenetti_2014) and observed at our laboratory (MEFV c.2177T>C, p.Val726Ala), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Furthermore, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of uncertain significance for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
The MEFV c.322A>C; p.Ser108Arg variant (rs104895103) is reported in the literature in multiple individuals with MEFV-related periodic fever syndromes and has been reported as compound heterozygous with the pathogenic V726A allele (Federici 2012, Gattorno 2009, Kilinc 2016, Medlej-Hashim 2005). This variant is classified as uncertain in ClinVar (Variation ID: 97515). It is only observed in two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on currently available information, it is uncertain whether this variant is benign or disease-associated. REFERENCES Federici S et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis. 2012 Dec;71(12):1961-5. Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. Kilinc M et al. The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int. 2016 Jan;36(1):25-31. Medlej-Hashim M et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000081). A missense variant is a common mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MEFV related disorder (PMID:16378925). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
The p.S108R variant (also known as c.322A>C), located in coding exon 2 of the MEFV gene, results from an A to C substitution at nucleotide position 322. The serine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in two individuals with FMF; one individual also had the p.V726A pathogenic mutation and the second individual had two additional alterations in the MEFV gene. The phase of these alterations (whether in cis or trans) is not known (Medlej-Hashim M, Eur J Med Genet ; 48(4):412-20). This variant was previously reported in the SNPDatabase as rs104895103. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Comment:
Observed in the heterozygous state in patients with MEFV-related periodic fever syndromes, often in individuals also heterozygous for the p.(V726A) variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Medlej-Hashim et al., 2005; Salehzadeh et al., 2014; Kilinc et al., 2016; Papa et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26215181, 25793047, 29047407, 23463692, 19786432, 22580583, 16378925, 33844039, El Hawary_2022)
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 108 of the MEFV protein (p.Ser108Arg). This variant is present in population databases (rs104895103, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 16378925, 19786432, 29047407). ClinVar contains an entry for this variant (Variation ID: 97515). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever. | Accetturo M | Rheumatology (Oxford, England) | 2020 | PMID: 31411330 |
| New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). | Van Gijn ME | Journal of medical genetics | 2018 | PMID: 29599418 |
| A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. | Papa R | Orphanet journal of rare diseases | 2017 | PMID: 29047407 |
| Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations. | Martorana D | Frontiers in immunology | 2017 | PMID: 28421071 |
| The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaraş) of Turkey. | Kilinc M | Rheumatology international | 2016 | PMID: 26215181 |
| Global epidemiology of Familial Mediterranean fever mutations using population exome sequences. | Fujikura K | Molecular genetics & genomic medicine | 2015 | PMID: 26247045 |
| PFAPA and 12 Common MEFV Gene Mutations Our Clinical Experience. | Salehzadeh F | Iranian journal of pediatrics | 2014 | PMID: 25793047 |
| The frequency of Familial Mediterranean fever gene mutations and genotypes at Kirikkale and comparison with the mean of regional MEFV mutation frequency of Turkey. | Sayın Kocakap DB | Molecular biology reports | 2014 | PMID: 24381109 |
| Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. | Omenetti A | Annals of the rheumatic diseases | 2014 | PMID: 23505242 |
| Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children. | Ozen S | Annals of the rheumatic diseases | 2014 | PMID: 23463692 |
| Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder. | Portincasa P | European journal of clinical investigation | 2013 | PMID: 24117178 |
| 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 |
| Familial Mediterranean fever--a review. | Shohat M | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21358337 |
| Differentiating PFAPA syndrome from monogenic periodic fevers. | Gattorno M | Pediatrics | 2009 | PMID: 19786432 |
| The population genetics of familial mediterranean fever: a meta-analysis study. | Papadopoulos VP | Annals of human genetics | 2008 | PMID: 18691160 |
| Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. | Medlej-Hashim M | European journal of medical genetics | 2005 | PMID: 16378925 |
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Text-mined citations for rs104895103 ...
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the rs number, so they may include citations for more than one variant
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.