This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the MEFV protein (p.Pro780Thr). This variant is present in population databases (rs104895154, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 16730661, 17665427). ClinVar contains an entry for this variant (Variation ID: 97511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine 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.
ClinVar Genomic variation as it relates to human health
NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr)
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.
(12)
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(7); Benign(3)
Uncertain significance(7); Benign(3)
12
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.2338C>A (p.Pro780Thr)
Variation ID: 97511 Accession: VCV000097511.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 3243149 (GRCh38) [ NCBI UCSC ] 16: 3293149 (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 Mar 4, 2023 Feb 8, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000243.3:c.2338C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000234.1:p.Pro780Thr missense NM_001198536.2:c.*542C>A 3 prime UTR NC_000016.10:g.3243149G>T NC_000016.9:g.3293149G>T NG_007871.1:g.18479C>A LRG_190:g.18479C>A LRG_190t1:c.2338C>A LRG_190p1:p.Pro780Thr O15553:p.Pro780Thr - Protein change
- P780T
- Other names
- -
- Canonical SPDI
- NC_000016.10:3243148:G:T
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- 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 |
960 | 1261 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Feb 8, 2023 | RCV000083763.15 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2022 | RCV000217446.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 14, 2022 | RCV002298469.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 26, 2021 | RCV002262642.3 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 8, 2023 | RCV003126467.1 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 8, 2023 | RCV003126468.1 |
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
(Feb 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543746.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Uncertain significance
(Aug 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001217160.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the MEFV protein (p.Pro780Thr). … (more)
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the MEFV protein (p.Pro780Thr). This variant is present in population databases (rs104895154, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 16730661, 17665427). ClinVar contains an entry for this variant (Variation ID: 97511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine 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. (less)
|
|
|
Uncertain significance
(May 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927692.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
|
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001277618.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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
(Sep 14, 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: SCV002598584.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: MEFV c.2338C>A (p.Pro780Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: MEFV c.2338C>A (p.Pro780Thr) 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 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2338C>A has been reported in the literature in individuals affected with Familial Mediterranean Fever (example, Gouliemos_2006, Canete_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279570.10
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
Identified in the literature (Goulielmos et al., 2006) to be associated with mild severity of familial Mediterranean fever; however, clinical information was not provided; Identified … (more)
Identified in the literature (Goulielmos et al., 2006) to be associated with mild severity of familial Mediterranean fever; however, clinical information was not provided; Identified in a patient with palindromic rheumatism in the literature (Canete et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665427, 16730661) (less)
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139802.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
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: SCV003802167.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Benign
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003802156.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
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: SCV003802178.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462090.1
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: SCV000115859.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
|
|
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Comment:
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:
Variant summary: MEFV c.2338C>A (p.Pro780Thr) 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 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2338C>A has been reported in the literature in individuals affected with Familial Mediterranean Fever (example, Gouliemos_2006, Canete_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Identified in the literature (Goulielmos et al., 2006) to be associated with mild severity of familial Mediterranean fever; however, clinical information was not provided; Identified in a patient with palindromic rheumatism in the literature (Canete et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665427, 16730661)
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:
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the MEFV protein (p.Pro780Thr). This variant is present in population databases (rs104895154, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 16730661, 17665427). ClinVar contains an entry for this variant (Variation ID: 97511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine 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.
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:
Variant summary: MEFV c.2338C>A (p.Pro780Thr) 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 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2338C>A has been reported in the literature in individuals affected with Familial Mediterranean Fever (example, Gouliemos_2006, Canete_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Identified in the literature (Goulielmos et al., 2006) to be associated with mild severity of familial Mediterranean fever; however, clinical information was not provided; Identified in a patient with palindromic rheumatism in the literature (Canete et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17665427, 16730661)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Review: Familial Mediterranean Fever-An Overview of Pathogenesis, Symptoms, Ocular Manifestations, and Treatment. | Petrushkin H | Ocular immunology and inflammation | 2016 | PMID: 25760918 |
| An unexpectedly high frequency of MEFV mutations in patients with anti-citrullinated protein antibody-negative palindromic rheumatism. | Cañete JD | Arthritis and rheumatism | 2007 | PMID: 17665427 |
| Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF). | Goulielmos GN | Biochemical and biophysical research communications | 2006 | PMID: 16730661 |
Text-mined citations for rs104895154 ...
HelpThese 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 Sep 29, 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.