chr16-3243257-C-A

Position:

• chr16-3243257-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM5 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. 15/21 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 Likely pathogenic.

• 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:25 U:13 O:2
• Conservation: PhyloP100: 0.648

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 3 ACMG points.

• PM1: In a domain B30.2/SPRY (size 195) in uniprot entity MEFV_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in NM_000243.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3243257-C-T is described in Lovd as [Likely_pathogenic].
• 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 id is 2548.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, not_provided=2, Uncertain_significance=9, Pathogenic=15}. Variant chr16-3243257-C-A is described in Lovd as [Pathogenic]. Variant chr16-3243257-C-A is described in Lovd as [Likely_pathogenic].
• 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 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/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2230G>T	p.Ala744Ser	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*434G>T		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.2230G>T	p.Ala744Ser	missense_variant	10/10	1	NM_000243.3	ENSP00000219596	P3

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

GnomAD3 exomes AF: 0.00184 AC: 463 AN: 251440 Hom.: 2 AF XY: 0.00182 AC XY: 247 AN XY: 135910

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 SAS exome AF: 0.000359

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

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00262

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00225 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:25 Uncertain:13 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:9 Uncertain:7

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MEFV: PM1:Strong, PM2:Supporting, PP1, PP4, BP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 26, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2021	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 22, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 20, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2023	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 Pathogenic:8 Uncertain:2 Other:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 31, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:2 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 21, 2022	- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 23, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 28, 2017	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. -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2024	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. -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 05, 2022

- -

MEFV-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2017

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;.;.
MutationTaster	Benign	1.0	D;N;N;N
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

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: rs61732874; hg19: chr16-3293257;