rs61732874

Variant names:

• chr16-3243257-C-A
• rs61732874
• NM_000243.3:c.2230G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3243257-C-A
• chr16-3243257-C-G
• chr16-3243257-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS2_Supporting

The NM_000243.3(MEFV):​c.2230G>T​(p.Ala744Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,614,092 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. A744T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:28 U:14 O:2
• Conservation: PhyloP100: 0.648
• Publications: 184 publications found

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]

MEFV Gene-Disease associations (from GenCC):

• familial Mediterranean fever

  Inheritance: AD, AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, ClinGen
• autosomal recessive familial Mediterranean fever

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• familial Mediterranean fever, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 16-3243257-C-A is Pathogenic according to our data. Variant chr16-3243257-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2548.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056206584). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2230G>T	p.Ala744Ser	missense_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*434G>T		3_prime_UTR_variant	Exon 9 of 9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.2230G>T	p.Ala744Ser	missense_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00184 AC: 463 AN: 251440 AF XY: 0.00182

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00164 AC: 2393 AN: 1461878 Hom.: 10 Cov.: 32 AF XY: 0.00163 AC XY: 1188 AN XY: 727238

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 344 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53412

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00144 AC: 1597 AN: 1112004

Other (OTH) AF: 0.00262 AC: 158 AN: 60396

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74410

African (AFR) AF: 0.000626 AC: 26 AN: 41526

American (AMR) AF: 0.00405 AC: 62 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67996

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00214 Hom.: 2

Bravo AF: 0.00231

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:28 Uncertain:14 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial Mediterranean fever Pathogenic:11 Uncertain:3 Other:2

May 18, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 31, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3_VeryStrong, PP4 -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 28, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Jan 20, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:7 Uncertain:7

Jun 23, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jun 02, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV: PM3:Very Strong, PM1, PM2:Supporting, BP4 -

Apr 26, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 (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: Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):473-83. -

Aug 10, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Familial Mediterranean fever, autosomal dominant Pathogenic:3 Uncertain:1

Aug 25, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:3

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 23, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

MEFV-related disorder Pathogenic:2

Aug 29, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2230G>T (p.Ala744Ser) variant affects a weakly conserved amino acid and in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a heterozygous and compound heterozygous change in patients with MEFV-related disorders (PMID: 29808155, 29543225, 23031807, 26843738, 20301405). The c.2230G>T (p.Ala744Ser) variant is located in the B30.2/SPRY domain, which is a known hotspot domain for pathogenic variations associated with MEFV-related disorders (PMID: 19302049, 28386255). The c.2230G>T (p.Ala744Ser) variant is present in the gnomAD v4 population database at a frequency of 0.16% (2655/1614092) in the heterozygous state and present in 10 individuals in the homozygous state. Based on the available evidence, this c.2230G>T (p.Ala744Ser) is classified as Likely Pathogenic. -

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0017 in 1615482 control chromosomes, predominantly at a frequency of 0.013 within the Latino subpopulation in the gnomAD database, including 10 homozygotes globally. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing autosomal recessive Familial Mediterranean Fever (0.0017 vs 0.022), allowing no conclusion about variant significance. However, this frequency exceeds the maximum pathogenic allele frequency for dominant FMF (0.0005). 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, Krieghauser_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). At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Honda_2021). The following publications have been ascertained in the context of this evaluation (PMID: 27884173, 19449169, 10090880, 15024744, 32401353, 33738724, 16439335, 9668175, 22614345, 16614989, 29735907, 33733382, 19253030, 30409984, 20008924, 16627024, 10737992, 25393764, 20165923, 39003954, 17566872, 25648235, 33726481, 20645115, 30476289, 14578331, 29599418, 20177433, 21413889, 23907647, 26843738, 23031807, 29543225). ClinVar contains an entry for this variant (Variation ID: 2548). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autoinflammatory syndrome Pathogenic:1

Apr 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:1

Nov 28, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Inborn genetic diseases Uncertain:1

Aug 23, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	1.1
DANN	Benign	0.21
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.6	N;.;.
PhyloP100		0.65
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.19
MVP		0.50
MPC		0.10
ClinPred		0.0043	T
GERP RS		-3.0
Varity_R		0.10
gMVP		0.11
Mutation Taster		=70/30	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61732874; hg19: chr16-3293257;