VCV000234502.12 - ClinVar

NM_000243.3(MEFV):c.1337A>C (p.Glu446Ala)

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.

(8)

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(5); Likely benign(2)

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.1337A>C (p.Glu446Ala)

Variation ID: 234502 Accession: VCV000234502.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3248928 (GRCh38) [ NCBI UCSC ] 16: 3298928 (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 8, 2017	Mar 4, 2023	Feb 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000243.3:c.1337A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000234.1:p.Glu446Ala	missense
NM_001198536.2:c.704A>C	NP_001185465.2:p.Glu235Ala	missense
NC_000016.10:g.3248928T>G
NC_000016.9:g.3298928T>G
NG_007871.1:g.12700A>C
LRG_190:g.12700A>C
LRG_190t1:c.1337A>C	LRG_190p1:p.Glu446Ala

... more HGVS ... less HGVS

Protein change

E446A, E235A

Other names

Canonical SPDI

NC_000016.10:3248927:T:G

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.

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

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00014

Links

ClinGen: CA7860180 dbSNP: rs749651486 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	956	1257

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 9, 2020	RCV000219419.4
Familial Mediterranean fever	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2023	RCV000632789.6
Autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2018	RCV002262826.3
Familial Mediterranean fever, autosomal dominant	Likely benign (1)	criteria provided, single submitter	Feb 8, 2023	RCV003126637.1
Acute febrile neutrophilic dermatosis Familial Mediterranean fever Familial Mediterranean fever, autosomal dominant	Uncertain significance (1)	criteria provided, single submitter	Jan 17, 2022	RCV002478821.1
Acute febrile neutrophilic dermatosis	Likely benign (1)	criteria provided, single submitter	Feb 8, 2023	RCV003126638.1

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 (Sep 09, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279390.9 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: 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
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: SCV002543701.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Jan 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002792336.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jun 12, 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: SCV000753977.3 First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 446 of the MEFV protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 446 of the MEFV protein (p.Glu446Ala). This variant is present in population databases (rs749651486, gnomAD 0.008%). 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: 234502). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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)
Likely benign (Feb 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: unknown Allele origin: germline	Genome-Nilou Lab Accession: SCV003802161.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Uncertain significance (Feb 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Genome-Nilou Lab Accession: SCV003802160.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Likely benign (Feb 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acute febrile neutrophilic dermatosis Affected status: unknown Allele origin: germline	Genome-Nilou Lab Accession: SCV003802162.1 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: SCV001452077.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 446 of the MEFV protein (p.Glu446Ala). This variant is present in population databases (rs749651486, gnomAD 0.008%). 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: 234502). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs749651486 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000243.3(MEFV):c.1337A>C (p.Glu446Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs749651486 ...