NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr) AND Familial Mediterranean fever

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Feb 8, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000083763.15

Allele description [Variation Report for NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr)]

NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr)

Gene:

MEFV:MEFV innate immunity regulator, pyrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000243.3(MEFV):c.2338C>A (p.Pro780Thr)

HGVS:

NC_000016.10:g.3243149G>T
NG_007871.1:g.18479C>A
NM_000243.3:c.2338C>AMANE SELECT
NM_001198536.2:c.*542C>A
NP_000234.1:p.Pro780Thr
NP_000234.1:p.Pro780Thr
LRG_190t1:c.2338C>A
LRG_190:g.18479C>A
LRG_190p1:p.Pro780Thr
NC_000016.9:g.3293149G>T
NM_000243.1:c.2338C>A
NM_000243.2:c.2338C>A
O15553:p.Pro780Thr

Protein change:

P780T

Links:

UniProtKB: O15553#VAR_028353; dbSNP: rs104895154

NCBI 1000 Genomes Browser:

rs104895154

Molecular consequence:

NM_001198536.2:c.*542C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.2338C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial Mediterranean fever (FMF)
Synonyms:: POLYSEROSITIS, FAMILIAL PAROXYSMAL; POLYSEROSITIS, RECURRENT; Periodic peritonitis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018088; MedGen: C0031069; Orphanet: 342; OMIM: 249100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000115859	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV001139802	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001217160	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16730661, 17665427, 28492532
SCV001277618	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16730661, 17665427 Citation Link,
SCV001462090	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV003802156	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Feb 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF).

Goulielmos GN, Fragouli E, Aksentijevich I, Sidiropoulos P, Boumpas DT, Eliopoulos E.

Biochem Biophys Res Commun. 2006 Jul 14;345(4):1326-32. Epub 2006 May 15.

PubMed [citation]

PMID:: 16730661

See all PubMed Citations (4)

Details of each submission

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000115859.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001139802.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001217160.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001277618.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001462090.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV003802156.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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