Submissions for variant NM_000243.3(MEFV):c.97G>T (p.Val33Leu)

gnomAD frequency: 0.00250  dbSNP: rs11466016

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589938	SCV000329418	uncertain significance	not provided	2022-02-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar with conflicting classifications (VCV000036516.14); Has not been reported in an affected patient in the published literature to our knowledge; This variant is associated with the following publications: (PMID: 28421071, 29178647, 32082075)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290446	SCV000696083	benign	not specified	2021-01-04	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.97G>T (p.Val33Leu) results in a conservative amino acid change located in the DAPIN (Domain in Apoptosis and INterferon response) domain (IPR004020) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 150956 control chromosomes, predominantly at a frequency of 0.0081 within the African subpopulation in the gnomAD database, including 4 homozygotes (gnomAD v3.1 genomes dataset). This frequency is somewhat lower than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.022), however the observed homozygous occurrences may still suggest a benign role for the variant. Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within the African Caribbeans in Barbados (ACB; 1%) and Mende in Sierra Leone (MSL; 1.8%) subpopulations, suggesting this variant is likely a benign polymorphism (Moradian_2017). To our knowledge, no occurrence of c.97G>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x), likely benign (1x) or benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768268	SCV000898828	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2017-11-21	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 1 p.Val33Leu (c.97G>T): This variant has not been reported in the literature but is present in 0.7% (191/24036) of African alleles including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs11466016). This variant is present in ClinVar (Variation ID:36516). This variant amino acid Leucine (Leu) is present in >40 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae	RCV000030189	SCV001097600	likely benign	Familial Mediterranean fever	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589938	SCV001158483	uncertain significance	not provided	2022-03-31	criteria provided, single submitter	clinical testing	The MEFV c.97G>T; p.Val33Leu variant (rs11466016), to our knowledge, is not reported in the medical literature in an affected individual but is reported in ClinVar (Variation ID: 36516). This variant is found in the African population with an allele frequency of 0.8% (199/24,970 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 33 is moderately conserved and computational analyses predict that this variant is neutral (REVEL: 0.11). However, due to limited information, the clinical significance of the p.Val33Leu variant is uncertain at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262594	SCV002542316	likely benign	Autoinflammatory syndrome	2021-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589938	SCV002822255	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MEFV: BP4, BS2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224110	SCV003920203	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-03-30	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 1 p.Val33Leu (c.97G>T): This variant has not been reported in the literature but is present in 0.7% (191/24036) of African alleles including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs11466016). This variant is present in ClinVar (Variation ID:36516). This variant amino acid Leucine (Leu) is present in >40 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV000589938	SCV004227519	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV001276303	SCV001462434	benign	Familial Mediterranean fever, autosomal dominant	2020-06-06	no assertion criteria provided	clinical testing