rs104895081

chr16-3254268-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000243.3(MEFV):c.800C>T(p.Thr267Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T267S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:8 O:2
• Conservation: PhyloP100: -1.98

Genes affected

MEFV (HGNC:6998): (MEFV innate immunity regulator, pyrin) This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 16-3254268-G-A is Pathogenic according to our data. Variant chr16-3254268-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2544.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=1, not_provided=2, Pathogenic=1}. Variant chr16-3254268-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEFV	NM_000243.3	c.800C>T	p.Thr267Ile	missense_variant	2/10	ENST00000219596.6
MEFV	NM_001198536.2	c.277+2043C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEFV	ENST00000219596.6	c.800C>T	p.Thr267Ile	missense_variant	2/10	1	NM_000243.3	P3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251456 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74510

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Pathogenic:1 Uncertain:3 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 267 of the MEFV protein (p.Thr267Ile). This variant is present in population databases (rs104895081, gnomAD 0.03%). This missense change has been observed in individual(s) with familial Mediterranean fever and/or juvenile idiopathic arthritis or other autoinflammatory conditions (PMID: 9668175, 10737992, 16378925, 17489852, 20485448, 21413889, 23505238, 23588594, 24469716, 26003477). ClinVar contains an entry for this variant (Variation ID: 2544). 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 isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MEFV function (PMID: 33733382). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	May 14, 2018	- -

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	Observed with a pathogenic variant on the same allele (in cis) in an individual with familial Mediterranean fever in published literature (Oztuzcu et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23505238, 20485448, 10737992, 25703702, 29178647, 28631068, 29314707, 29599418, 23588594, 16378925, 17384215, 11175300, 9668175, 26247045, 22975760, 29260407, 27457448, 28386255, 28624931, 27051312, 29735907, 29200027, 30488432, 20721559, 20645115, 15951859, 26003477, 34426522, 33733382, 36223753, 17489852, 24469716, 11781702) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: MEFV c.800C>T (p.Thr267Ile) 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 0.00016 in 251456 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever, allowing no conclusion about variant significance. c.800C>T has been reported in the literature in homozygous, compound heterozygous, complex compound heterozygous and heterozygous genotypes, in studies of multiple individuals affected with and/or meeting established clinical criteria of Familial Mediterranean Fever (e.g. Bernot_1998, Ceylan_2012, Cornelius_2010, Dogan_2015, Giaglis_2007, Medlej-Hashim_2000, Moradian_2010). The extent of genotyping reported was variable ranging from targeted analysis to full sequencing of the MEFV gene. At-least one of these reports included a patient in whom two other bonafide pathogenic variants that are well reported as causative of FMF, namely p.Met694Val and p.Val726Ala were identified (Cornelius_2010). In 2012, a group of clinical and molecular experts reached a consensus to test for a total of 14 MEFV variants, including p.Thr267Ile which they described as clearly pathogenic (Shinar_2012). In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of likely pathogenic for this variant (Van Gijn_2018). One experimental study reported no substantial increase in spontaneous cell death and TcdA/UCN-01-induced cell death enhancement due to the variant in transfected cells (Honda_2021). ClinVar contains an entry for this variant (Variation ID: 2544). Our laboratory classified this variant as 'pathogenic' in 2016 weighting the expert panel opinion (Shinar_2012) and reports of its presence in patients with clinically or suspected diagnosis of FMF. However, the prevailing consensus for this variant when observed in a clinical diagnostic setting seems to have shifted to an uncertain significance. Based on the evidence outlined above, the variant was re-classified as a VUS-possibly pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2019	The MEFV c.800C>T; p.Thr267Ile variant (rs104895081) has been published in the literature in individuals with familial Mediterranean fever (FMF) or juvenile idiopathic arthritis, with or without another pathogenic variant (Bernot 1998, Ceylan 2012, Comak 2013, Dogan 2015, Giaglis 2007, Oztuzcu 2014). This variant is listed in the ClinVar database (Variation ID: 2544) and listed in the general population with an overall allele frequency of 0.015% (42/282848 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Dogan H et al. Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. Gene. 2015 Sep 1;568(2):170-5. Giaglis S et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7. -

Familial Mediterranean fever, autosomal dominant Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 24, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Autoinflammatory syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 02, 2021

- -

MEFV-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The MEFV c.800C>T variant is predicted to result in the amino acid substitution p.Thr267Ile. This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD. It been reported in the homozygous state in an individual with familial Mediterranean fever (FMF) (Giaglis et al. 2007. PubMed ID: 17489852) and in the presence of a second MEFV variant; however, phase was not reported (Moradian et al. 2010. PubMed ID: 20485448; Oztuzcu et al. 2014. PubMed ID: 24469716). This variant was also reported in an individual with FMF and two other established pathogenic MEFV variants; however, the phase of this complex allele was not reported (Cornelius and Duno 2011. PubMed ID: 20721559). The c.800C>T (p.Thr267Ile) variant and another MEFV variant were reported in an individual with oligoarthritis; however, phase of the variants was not reported (Comak et al. 2013. PubMed ID: 23588594). This variant has been reported in the heterozygous state in individuals with FMF in which a second MEFV variant was not found or additional information on other variants was not provided (NAJ: 21-31, Bernot et al. 1998. PubMed ID: 9668175; Medlej-Hashim et al. 2005. PubMed ID: 16378925; Ceylan et al. 2012. PubMed ID: 22614345; Oztuzcu et al. 2014. PubMed ID: 24469716; Balta et al. 2020. PubMed ID: 31989427). Of note, FMF symptoms in patients with a single heterozygous MEFV variant could be due to an undetected second variant present in the gene or some patients with a single heterozygous variant could be mildly affected (Moradian et al. 2010. PubMed ID: 20485448). An in vitro functional study of monocytes expressing MEFV variants utilized flow cytometry to evaluate the impact the variants had on cell death showed that the p.Thr267Ile variant did not alter cell death rates and results were similar to that of wild type MEFV (Honda et al. 2021. PubMed ID: 33733382). Previous classifications of this variant determined it was causative (Shinar et al. 2012. PubMed ID: 22661645; Van Gijn et al. 2018. PubMed ID: 29599418; INFEVERS database); however, more recent classifications suggest this variant is of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/2544/). PreventionGenetics classified this variant as ‘pathogenic’ in 2015 based on the literature available at the time; however, based on current evidence the classification of this variant has shifted and now the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.054
Dann	Benign	0.94
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	3.4e-12	A;A;A;A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.32
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.65
MVP		0.36
MPC		0.13
ClinPred		0.031	T
GERP RS		-4.3
Varity_R		0.031
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104895081; hg19: chr16-3304268;