Submissions for variant NM_000243.3(MEFV):c.2230G>T (p.Ala744Ser)

dbSNP: rs61732874

Total submissions: 38

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000999738	SCV000052845	uncertain significance	not specified	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2230G>T (p.Ala744Ser) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 252830 control chromosomes, with 2 homozygotes. The variant occurs predominantly at a frequency of 0.013 within the confined population of Ashkenazi Jewish in the gnomAD database. A study conducted using data from the National Center for FMF in Israel, estimated the total frequency of FMF allele occurrence in ASJ population to be 1:161 (i.e. 0.0062) (Lidar_2010). The reported allele frequency of c.2230G>T in the ASJ population in the gnomAD database is 2-fold of the estimated total frequency of FMF allele occurrence in ASJ (0.013 vs. 0.0062), suggesting that the variant is a benign polymorphism. Furthermore, recent studies in Arabic individuals (a population not represented in the gnomAD database) report the variant as benign/likely benign based on a population frequency of >1% and its presence in the homozygous state in multiple individuals who lack the FMF phenotype (Abouelhoda_2016, John_2018, Alsubaie_2020). Further evidence in support of benign polymorphism comes from Alsubaie et al (2020) reporting absence of favorable response to 6 months of colchicine therapy in two heterozygous cases with a clinical picture resembling FMF. c.2230G>T has been reported in the literature in the heterozygous, compound heterozygous or homozygous state in multiple individuals reported with symptoms of Familial Mediterranean Fever (e.g. Bernot_1998, Aksentijevich_1999, Tchernitchko_2003, Sabbagh_2008, Akin_2010, Jarjour_2010, Ozdemir_2011, Ceylan_2012, Neocleous_2015, Salehzadeh_2015, Mattit_2016, Gumus_2018, Sari_2021) but has also been reported in healthy controls (e.g. Aldea_2004, Simsek_2011, John_2018). Many of these studies (especially earlier publications which led to the classification of the variant as pathogenic by multiple clinical providers), utilized only a restricted panel of variants or limited sequencing for targeted testing of individuals, and a large number of studies do not specify usage of Tel Hashomer clinical criteria to confirm diagnosis of FMF. In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of uncertain significance for the variant (Van Gijn_2018). Therefore, these reports do not allow 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. Many clinical-significance assessments for this variant have been submitted to ClinVar after 2014. A majority (18 of 23) cite the variant as pathogenic/likely pathogenic and five ClinVar submitters cite the variant as uncertain significance. However, it is not clear how many submitters considered the recent reports by Alsubaie_2020 and Van Gijn_2018 in the context of their evaluation. Based on recent evidence that became available as outlined above, the variant was re-classified as uncertain significance from a previous classification of pathogenic.
GeneDx	RCV000213702	SCV000279063	uncertain significance	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Reported previously in either the homozygous state or along with another pathogenic MEFV variant in association with familial Mediterranean fever in families of various ancestries in published literature and referred for genetic testing at GeneDx (Aksentijevich, 1999; Bernot et al., 1998; Rodriguez-Flores et al., 2014; Moradian et al., 2014; Caglayan et al., 2010; Oztuzcu et al., 2014; Oksuz et al., 2016); Modeling studies of the pyrin protein indicate that the variant may affect folding of the binding cavity or impair interaction with other molecules (Goulielmos et al., 2006); however, in the absence of functional studies, the actual effect of this sequence change is unknown; Listed in ClinVar with conflicting classification (VCV000002548); This variant is associated with the following publications: (PMID: 28943464, 31804137, 22975760, 27884173, 24123366, 20041150, 9668175, 27659338, 28927886, 26360812, 28573371, 30487145, 29543225, 26843738, 30783801, 22903357, 23031807, 31171010, 31692716, 30915208, 33440462, 29080837, 29808155, 16730661, 10090880, 33738724, 32401353)
Eurofins Ntd Llc (ga)	RCV000213702	SCV000331539	pathogenic	not provided	2017-06-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000002657	SCV000396760	pathogenic	Familial Mediterranean fever	2017-04-27	criteria provided, single submitter	clinical testing	The MEFV c.2230G>T (p.Ala744Ser) missense variant is well described in the literature as a pathogenic variant for familial Mediterranean fever (FMF). The variant has been reported in at least 12 studies in which it is found in at least 141 patients with FMF, including one homozygote, 26 compound heterozygotes, and 114 heterozygotes, plus an additional 56 of 4624 patient alleles where zygosity information is not provided (Bernot et al. 1998; Aksentijevich et al. 1999; Tchernitchko et al. 2003; Caglayan et al. 2010; Medlej-Hashim et al. 2010; Ait-Idir et al. 2011; Kilim et al. 2011; Ozdemir et al. 2011; Belmahi et al. 2012; Yesilad et al. 2012; Habahbeh et al. 2015; Salehzadeh et al. 2015). Across these studies, the variant was also reported in seven out of 950 control alleles. The p.Ala744Ser variant is also reported at a frequency of 0.01869 in the Iberian Populations in Spain cohort in the 1000 Genomes Project. This allele frequency is high but is consistent with estimates of disease prevalence. Based on the collective evidence, the p.Ala744Ser variant is classified as pathogenic for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000213702	SCV000604174	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The MEFV c.2230G>T; p.Ala744Ser variant (rs61732874) is reported as a common pathogenic variant in the literature, and is present in multiple individuals affected with Familial Mediterranean Fever (Beheshtian 2016, Habahbeh 2015, Salehzadeh 2015, Touitou 2001). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 2548), and is found in the general population with an overall allele frequency of 0.18% (499/282,842 alleles, including 2 homozygotes) in the Genome Aggregation Database. Based on available information, the p.Ala744Ser variant is considered to be pathogenic. REFERENCES Beheshtian M et al. Prevalence of common MEFV mutations and carrier frequencies in a large cohort of Iranian populations. J Genet. 2016 Sep;95(3):667-74. Habahbeh LA et al. Genetic Profile of Patients with Familial Mediterranean Fever (FMF): Single Center Experience at King Hussein Medical Center (KHMC). Med Arch. 2015 Dec;69(6):417-20. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):473-83.
CeGaT Center for Human Genetics Tuebingen	RCV000213702	SCV000608743	likely pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MEFV: PM1:Strong, PM2:Supporting, PP1, PP4, BP4
Invitae	RCV000002657	SCV000629039	pathogenic	Familial Mediterranean fever	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 744 of the MEFV protein (p.Ala744Ser). This variant is present in population databases (rs61732874, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MEFV-related conditions (PMID: 17566872, 19449169, 19934083, 20177433, 23031807, 25793047, 26843738). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2548). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768020	SCV000898821	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2017-11-28	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 10 p.Ala744Ser (c.2230G>T): This variant is a well reported pathogenic variant in the literature (including a GeneReviews entry) and has been identified in several individuals with Familial Mediterranean Fever (FMF) (Bernot 1998 PMID:9668175, Aksentijevich 1999 PMID:10090880, Caglayan 2010 PMID:19934083, Ait-Idir 2011 PMID:22019805, Salehzadeh 2015 PMID:25648235, Shohat 2016 PMID:20301405). This variant is present in 1% (129/10152) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61732874). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2548). In summary, despite the presence of conflicting data (i.e. high frequency in the population, non-conserved amino acid position), this is consistent with the expected disease prevalence and carrier status of this condition. Therefore this variant is classified as pathogenic.
Mendelics	RCV000002657	SCV001139810	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002657	SCV001193781	likely pathogenic	Familial Mediterranean fever	2019-12-31	criteria provided, single submitter	clinical testing	NM_000243.2(MEFV):c.2230G>T(A744S) is classified as likely pathogenic in the context of familial Mediterranean fever. Please note that In the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV mutation status is uncertain. Sources cited for classification include the following: PMID 28590056, 20008924, 27659338, 27884173, 22019805, 23716950, 15024744, 19863562, 22661645, 19786432, 19934083, 26843738, 23031807, 20177433 and 19449169. Classification of NM_000243.2(MEFV):c.2230G>T(A744S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000213702	SCV001447980	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000213702	SCV001450225	likely pathogenic	not provided	2017-04-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002657	SCV001737246	likely pathogenic	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535864	SCV001752479	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000213702	SCV002017262	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000213702	SCV002502688	likely pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing
3billion	RCV000002657	SCV002521132	pathogenic	Familial Mediterranean fever	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.176%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002548). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 17566872, 19934083). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000213702	SCV002541304	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262547	SCV002543741	pathogenic	Autoinflammatory syndrome	2022-04-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415388	SCV002725393	uncertain significance	Inborn genetic diseases	2017-08-23	criteria provided, single submitter	clinical testing	The p.A744S variant (also known as c.2230G>T), located in coding exon 10 of the MEFV gene, results from a G to T substitution at nucleotide position 2230. The alanine at codon 744 is replaced by serine, an amino acid with similar properties. This variant has been reported in individuals with a clinical diagnosis of familial Mediterranean fever alone or in conjunction with a second MEFV alteration; however, the phase (whether in cis or trans) is not known (Bernot A et al. Hum. Mol. Genet., 1998 Aug;7:1317-25; Aksentijevich I et al. Am. J. Hum. Genet., 1999 Apr;64:949-62; Giaglis S et al. Clin. Genet., 2007 May;71:458-67; Caglayan AO et al. Nephrol. Dial. Transplant., 2010 Aug;25:2520-3). In addition, an individual undergoing carrier screening for another disorder was found to be homozygous for this variant (Mikula M et al. Genet. Med., 2008 May;10:349-52). This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000213702	SCV002818146	likely pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002657	SCV003836437	pathogenic	Familial Mediterranean fever	2022-03-18	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001535864	SCV003920205	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-11-23	criteria provided, single submitter	clinical testing	MEFV NM_000243 exon 10 p.Ala744Ser (c.2230G>T): This variant is a well reported pathogenic variant in the literature (including a GeneReviews entry) and has been identified in several individuals with Familial Mediterranean Fever (FMF) (Bernot 1998 PMID:9668175, Aksentijevich 1999 PMID:10090880, Caglayan 2010 PMID:19934083, Ait-Idir 2011 PMID:22019805, Salehzadeh 2015 PMID:25648235, Shohat 2016 PMID:20301405). This variant is present in 1% (129/10152) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61732874). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2548). In summary, despite the presence of conflicting data (i.e. high frequency in the population, non-conserved amino acid position), this is consistent with the expected disease prevalence and carrier status of this condition. Therefore this variant is classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001770031	SCV004045785	pathogenic	Familial Mediterranean fever, autosomal dominant	2022-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532274	SCV004121107	pathogenic	MEFV-related disorder	2024-02-24	criteria provided, single submitter	clinical testing	The MEFV c.2230G>T variant is predicted to result in the amino acid substitution p.Ala744Ser. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple individuals with familial Mediterranean fever (Bernot et al. 1998. PubMed ID: 9668175; Giaglis et al. 2007. PubMed ID: 17489852; Gattorno et al. 2009. PubMed ID: 19786432; Rodriguez-Flores et al. 2013. PubMed ID: 24123366; Salehzadeh et al. 2015. PubMed ID: 25648235; Stella et al. 2019. PubMed ID: 30476289; Umar et al. 2020. PubMed ID: 32853466; Fathalla et al. 2021. PubMed ID: 33440462; Sarı et al. 2021. PubMed ID: 33726481). However, this variant has also been reported in the heterozygous state in healthy control populations (Aldea et al. 2004. PubMed ID: 15024744; Table 7, John et al. 2018. PubMed ID: 30409984; Alsubaie et al. 2020. PubMed ID: 32401353). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been observed at a frequency of 4.2% in an Arabic population study (Alsubaie et al. 2020. PubMed ID: 32401353). Based on the reported allele frequency, this variant is potentially more common than expected for a causative variant. Of note, two homozygotes were observed in gnomAD and a few other homozygous asymptomatic individuals have been reported in the literature (Alsubaie et al. 2020. PubMed ID: 32401353; John et al. 2018. PubMed ID: 30409984). This may indicate this variant has reduced penetrance or variable expressivity in the homozygous state. An in vitro experimental study suggests this variant does not impact protein function (Honda et al. 2021. PubMed ID: 33733382). Of note, this variant has been reported as a variant of uncertain significance in the Infevers database (https://infevers.umai-montpellier.fr/web/index.php; Van Gijn et al. 2018. PubMed ID: 29599418). In ClinVar, the interpretation regarding the pathogenicity of this variant ranges from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/2548/), however the majority of submissions favor pathogenicity. Taken together, we interpret this variant as pathogenic for autosomal recessive MEFV-related disorders.
Baylor Genetics	RCV001770031	SCV004194403	likely pathogenic	Familial Mediterranean fever, autosomal dominant	2023-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213702	SCV004220020	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing	This variant has been identified in multiple individuals with Familial Mediterranean Fever (FMF) (PMID: 17566872 (2008), 23716950 (2012), 26005881 (2015), 29735907 (2018), 30476289 (2019), 32824452 (2020), 33738724 (2021), 34606655 (2021), 35098403 (2022)). However, individuals homozygous for this variant have been reported as being unaffected by FMF (PMID: 32401353 (2020)). Therefore, the A744S variant could be a variant with a mild effect on pyrin function or it could be a benign variant. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000002657	SCV004806538	uncertain significance	Familial Mediterranean fever	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213702	SCV004847547	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: infevers VUS, variant aa present in at least 3 mammals (2 primates). I keep it as VUS simply because eof the numerous reports, however the conservation data as well as frequency in Arab population make it unlikely to be clinically significant. ACMG/AMP Criteria applied: BP4_strong.
OMIM	RCV000002657	SCV000022815	pathogenic	Familial Mediterranean fever	1998-08-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000002657	SCV000115851	not provided	Familial Mediterranean fever		no assertion provided	not provided
GeneReviews	RCV000002657	SCV000484973	not provided	Familial Mediterranean fever		no assertion provided	literature only
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000768020	SCV001448268	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2020-10-04	flagged submission	clinical testing
Natera, Inc.	RCV000002657	SCV001462092	pathogenic	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000213702	SCV001929688	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000213702	SCV001962934	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000213702	SCV001970602	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770031	SCV002011780	uncertain significance	Familial Mediterranean fever, autosomal dominant	2021-08-25	no assertion criteria provided	clinical testing