NM_000243.3:c.2080A>G

Variant names:

• chr16-3243407-T-C
• rs61752717
• NM_000243.3:c.2080A>G
• MEFV p.Met694Val

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1PS3PM5PP5_Strong

The NM_000243.3(MEFV):c.2080A>G (p.Met694Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000177 (AC=285) in the gnomAD database across 1,614,154 control chromosomes, including 3 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00345. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000629034: Experimental studies have shown that this missense change affects MEFV function (PMID:24318677)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.M694I: Pathogenic/Likely_pathogenic (ClinVar VariationId 2539, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M694K: Uncertain_significance (ClinVar VariationId 803180, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 97487, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 3689508, 1 star); p.M694dup: Uncertain_significance (ClinVar VariationId 1785563, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Familial mediterranean fever (fmf).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: MEFV NM_000243.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:57 O:2
• Conservation: PhyloP100: 0.527
• Publications: 9 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):

• autosomal recessive familial Mediterranean fever

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

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women's Health, Natera, ClinGen, Orphanet, PanelApp Australia
• familial Mediterranean fever, autosomal dominant

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 1 star).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000629034: Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677).; SCV000803512: Well-established functional studies show a deleterious effect (PMID:24318677).; SCV003841560: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797).; SCV004847545: in vitro functional studies show decreased capacity of the variant protein to suppress IL-8 secretion in synovial cell cultures and FMF-knock-in mice studies showed decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, thereby providing some evidence that this variant impacts protein function (Sugiyama 2014 PMID: 24318677, Park 2016 PMID: 27270401).; SCV005060943: Functional studies of this variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama et al. 2014).; SCV005397676: In vivo studies of this variant in human and murine cells indicate that this variant stimulates the release of pro-inflammatory signals (PMID: 24318677, 21600797).; SCV000279058: Multiple published functional and FMF-knock-in mice studies demonstrated the damaging effect of the M694V variant, e.g., showing loss of suppression of IL-8 secretion in vitro (Sugiyama et al., 2014) and decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo (Park, 2016);; SCV000604181: Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014).; SCV001550173: Further, functional studies of the M694V variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama_2014_PMID:24318677).; SCV004046213: Functional studies have shown that this missense change has a damaging effect on the function of the MEFV protein (PMID: 24318677, 27270401).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.M694I: Pathogenic/Likely_pathogenic (ClinVar VariationId 2539, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.M694K: Uncertain_significance (ClinVar VariationId 803180, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 97487, 1 star); p.M694L: Uncertain_significance (ClinVar VariationId 3689508, 1 star); p.M694dup: Uncertain_significance (ClinVar VariationId 1785563, 1 star)
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (57/57 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000243.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MEFV NM_000243.3	MANE Select	c.2080A>G p.Met694Val	missense	Exon 10 of 10	Prot: NP_000234.1 UniProt:
	MEFV NM_001198536.2		c.*284A>G	3_prime_UTR	Exon 9 of 9	Prot: NP_001185465.2 UniProt:

MEFV NM_000243.3

MANE Select

HGVSc / HGVSpc.2080A>Gp.Met694Val

Exon rankExon 10 of 10

missense

Prot: NP_000234.1UniProt: O15553-2

MEFV NM_001198536.2

HGVSc / HGVSpc.*284A>G

Exon rankExon 9 of 9

3_prime_UTR

Prot: NP_001185465.2UniProt: D2DTW2O15553-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MEFV ENST00000219596.6	TSL:1MANE Select	c.2080A>G p.Met694Val	missense	Exon 10 of 10	Prot: ENSP00000219596.1 UniProt:
	MEFV ENST00000541159.5	TSL:1	c.*284A>G	3_prime_UTR	Exon 9 of 9	Prot: ENSP00000438711.1 UniProt:
	MEFV ENST00000539145.5	TSL:1	n.*713A>G	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000444471.1 UniProt:

MEFV ENST00000219596.6

TSL:1MANE Select

HGVSc / HGVSpc.2080A>Gp.Met694Val

Exon rankExon 10 of 10

missense

Prot: ENSP00000219596.1UniProt: O15553-2

MEFV ENST00000541159.5

TSL:1

HGVSc / HGVSpc.*284A>G

Exon rankExon 9 of 9

3_prime_UTR

Prot: ENSP00000438711.1UniProt: O15553-3

MEFV ENST00000539145.5

TSL:1

HGVSc / HGVSpn.*713A>G

Exon rankExon 7 of 7

3_prime_UTR

Prot: ENSP00000444471.1UniProt: F6TF35

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000131	AC:20	Hom:0	AN:152154	Cov:32
GnomAD2 exomes	AF: 0.000282	AC:71	Hom:	AN:251478	Cov:
GnomAD4 exome	AF: 0.000181	AC:265	Hom:3	AN:1461882	Cov:32
GnomAD4 genome	AF: 0.000131	AC:20	Hom:0	AN:152272	Cov:32
TOPMed (Bravo)	AF: 0.000223	AC:59	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000251	AC:97	Hom:1	AN:386010	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000231	AC:3	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00570	AC:1	Hom:	AN:176	Cov:
Turkish Variome	AF: 0.0180	AC:121	Hom:1	AN:6720	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000180 *	2	11112	0.00 *	0	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.000238	10	41958	0.000224	15	66888
SCHEMA(Schizophrenia)	0.000116	13	112434	0.000158	30	189404

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Familial Mediterranean fever (20)
17	-	-	not provided (17)
12	-	-	Familial Mediterranean fever, autosomal dominant (12)
3	-	-	MEFV-related disorder (3)
2	-	-	Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant (2)
1	-	-	Acute febrile neutrophilic dermatosis (1)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Recurrent fever (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.76	D
GPN-Star LLR	N/A	-3.4
GPN-Star score	N/A	3.4
LIST_S2	Benign	0.026	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.89	T
Mutation Taster	N/A	21/79	disease causing (ClinVar)
MutationAssessor	Benign	0.64	N
PhyloP100	Benign	0.53
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Varity_R	N/A	0.43
VESM-3B	Benign	-4.6

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs61752717;

hg19: chr16-3293407;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar