NM_000243.3(MEFV):c.1894G>A (p.Gly632Ser) AND Familial Mediterranean fever

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Mar 30, 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:: RCV000083719.17

Allele description [Variation Report for NM_000243.3(MEFV):c.1894G>A (p.Gly632Ser)]

NM_000243.3(MEFV):c.1894G>A (p.Gly632Ser)

Genes:

LOC126862264:CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:3293322-3294521 [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.1894G>A (p.Gly632Ser)

HGVS:

NC_000016.10:g.3243593C>T
NG_007871.1:g.18035G>A
NM_000243.3:c.1894G>AMANE SELECT
NM_001198536.2:c.*98G>A
NP_000234.1:p.Gly632Ser
NP_000234.1:p.Gly632Ser
LRG_190t1:c.1894G>A
LRG_190:g.18035G>A
LRG_190p1:p.Gly632Ser
NC_000016.9:g.3293593C>T
NM_000243.1:c.1894G>A
NM_000243.2:c.1894G>A
O15553:p.Gly632Ser

Protein change:

G632S

Links:

UniProtKB: O15553#VAR_028335; dbSNP: rs104895128

NCBI 1000 Genomes Browser:

rs104895128

Molecular consequence:

NM_001198536.2:c.*98G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000243.3:c.1894G>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
SCV000115811	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV000678115	Counsyl	no assertion criteria provided	Uncertain significance (Feb 14, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17938136, 24469716, 25286988, 23137073, 23633568, 27310525
SCV000696055	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 22, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26247045, 23633568, 24469716, 23137073, 17938136, 25286988 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001139839	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002498656	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 30, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17938136, 23137073, 23862117, 24469716, 27310525, 33738724, 25741868
SCV003522403	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 23, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16730661, 17938136, 24469716, 25286988, 27310525, 27473114, 28492532

Help

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

Global epidemiology of Familial Mediterranean fever mutations using population exome sequences.

Fujikura K.

Mol Genet Genomic Med. 2015 Jul;3(4):272-82. doi: 10.1002/mgg3.140. Epub 2015 Apr 5.

PubMed [citation]

PMID:: 26247045
PMCID:: PMC4521964

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease.

Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, Gutierrez-Cruz G, Kim Y, et al.

Proc Natl Acad Sci U S A. 2013 May 14;110(20):8134-9. doi: 10.1073/pnas.1306352110. Epub 2013 Apr 30.

PubMed [citation]

PMID:: 23633568
PMCID:: PMC3657824

See all PubMed Citations (13)

Details of each submission

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000115811.1

#	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 Counsyl, SCV000678115.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696055.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: The MEFV c.1894G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Ser. One structual study predicted this variant to be stabilizing (Arakelov_2015) and 3/4 in-silico tools predict this variant to be benign; however, functional studies have not been carried out to confirm these findings and in silico predictions are known to have low sensitivity and specificity for immunological gene variants. This variant is found in 5/122392 control chromosomes at a frequency of 0.0000409, which does not exceed the maximal expected frequency of a pathogenic allele (0.0216506) in this gene. No homozygotes have been reported in general population. The variant has been reported in at least eight FMF patients, one known to be compound heterozygous for a known pathogenic variant and three were homozygous for the variant. One family reported by Shinar_2007 also showed an indication that this variant cosegregated with disease. These patient data strongly suggests for a pathogenic outcome. This variant was also found in patients with adult-onset Stills disease and Behcet disease. The variant is considered a mild pathogenic mutation (Shinar_2007). Taken together, this variant has currently been classified as a Likely Pathogenic.

#	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 Mendelics, SCV001139839.1

#	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 Molecular Genetics, Royal Melbourne Hospital, SCV002498656.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change is predicted to replace glycine with serine at codon 632 of the MEFV protein (p.(Gly632Ser)). The glycine residue is not conserved (100 vertebrates, UCSC), and is located in the B30.2/SPRY domain. There is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with a recessive condition (10/274,946 alleles, 0 homozygotes in gnomAD v2.1). It has been identified heterozygous (alone), homozygous, and with a second MEFV allele in multiple cases with familial Mediterranean fever (FMF), and has been reported to segregate with disease dominantly in a single family with incomplete penetrance PMID: 17938136, 23137073, 24469716, 27310525). Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Another missense variant at this position (p.(Gly632Ala)) has been identified in Turkish FMF cases (PMID: 23862117, 33738724). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3_Strong, PM2_Supporting, BP4.

#	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 Invitae, SCV003522403.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 632 of the MEFV protein (p.Gly632Ser). This variant is present in population databases (rs104895128, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive MEFV-related conditions (PMID: 16730661, 17938136, 24469716, 25286988, 27310525, 27473114). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97467). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine 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

Last Updated: Aug 25, 2024

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