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

dbSNP: rs61732874

Total submissions: 42

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	2024-08-08	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 0.0017 in 1615482 control chromosomes in the gnomAD database (v4), including 10 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0017 vs 0.022). The variant occurs predominantly at a frequency of about 0.015 within the confined populations of Ashkenazi Jewish and Middle Eastern in the gnomAD database (v4). 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. The following publications have been ascertained in the context of this evaluation (PMID: 10090880, 9668175, 16439335, 14578331, 19449169, 15024744, 19253030, 20165923, 20645115, 16614989, 17566872, 10737992, 16627024, 22614345, 25393764, 25648235, 27884173, 29735907, 29599418, 30476289, 32401353, 30409984, 20008924, 33738724, 33726481). ClinVar contains an entry for this variant (Variation ID: 2548). Based on the evidence outlined above, the variant was classified as uncertain significance.
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	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	MEFV: PM3:Very Strong, PM1, PM2:Supporting, BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002657	SCV000629039	pathogenic	Familial Mediterranean fever	2025-02-03	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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001770031	SCV001448268	pathogenic	Familial Mediterranean fever, autosomal dominant	2020-10-04	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, Medical Genetics	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	RCV000002657	SCV002818146	likely pathogenic	Familial Mediterranean fever	2024-10-04	criteria provided, single submitter	research	PM3_VeryStrong, PP4
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
Baylor Genetics	RCV001770031	SCV004194403	likely pathogenic	Familial Mediterranean fever, autosomal dominant	2024-03-30	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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000999738	SCV005090185	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000002657	SCV005198748	uncertain significance	Familial Mediterranean fever	2025-01-20	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000002657	SCV005387570	likely pathogenic	Familial Mediterranean fever	2020-05-28	criteria provided, single submitter	clinical testing	This missense variant (c.2230G>T, p.Ala744Ser) has been observed at low frequency in population databases (gnomAD) and reported in the literature (PMID:30915208, 16730661, 2401353, 15024744, 16378925, 24929125). The p.Ala744Ser variant has been frequently reported and considered pathogenic by other laboratories, but due to lack of functional studies regarding the impact of this variant on gene function, this variant did not meet ACMG criteria for pathogenic in our assessment. It was identified in an affected patient.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002657	SCV005398560	pathogenic	Familial Mediterranean fever	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReview). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine (exon 10). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (495 heterozygotes, 2 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (4 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (SPRY domain; PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar). Variant reported in FMF patients in both heterozygous and homozygous state however, in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this variant may be uncertain. (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N)
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
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
PreventionGenetics, part of Exact Sciences	RCV004532274	SCV004121107	likely pathogenic	MEFV-related disorder	2024-08-22	no assertion criteria provided	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 (FMF) (Bernot et al. 1998. PubMed ID: 9668175; Aksentijevich et al. 1999. PubMed ID: 10090880; Tchernitchko et al. 2003. PubMed ID: 14578331; Giaglis et al. 2007. PubMed ID: 17489852; Gattorno et al. 2009. PubMed ID: 19786432; Stella et al. 2019. PubMed ID: 30476289; Ceylan et al. 2012. PubMed ID: 22614345; Salehzadeh et al. 2015. PubMed ID: 25648235; Fathalla et al. 2021. PubMed ID: 33440462). Of note, individuals with a clinical presentation of FMF and the c.2230G>T (p.Ala744Ser) in the heterozygous state did not show a response after six months of colchicine therapy (Alsubaie et al. 2020. PubMed ID: 32401353) and in another study this variant was only associated with features of FMF when in the compound heterozygous state with another MEFV complex allele (Family B, Stella et al. 2019. PubMed ID: 30476289). This variant has also been reported in healthy control populations (Aldea et al. 2004. PubMed ID: 15024744; Table 7, John et al. 2018. PubMed ID: 30409984). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. A retrospective analysis of the c.2230G>T (p.Ala744Ser) variant in Saudi Arabian individuals observed this variant at a frequency of 4.2% in the study population and of those tested few had features consistent with FMF or were asymptomatic (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 homozygous individuals were observed in gnomAD and 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. In-silico functional prediction tools suggest this variant has no impact on protein function and an in vitro experimental study showed this variant does not impact protein function (Honda et al. 2021. PubMed ID: 33733382). 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) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging 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 likely pathogenic for autosomal recessive MEFV-related disorders.