ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.97G>T (p.Val33Leu) (rs11466016)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589938 SCV000329418 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing To our knowledge, the V33L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The variant is observed in 191/24036 (0.79%) alleles from individuals of African background in large population cohorts, including one homozygote (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
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 2020-12-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001303 SCV001158483 uncertain significance none provided 2020-04-20 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 but is reported as uncertain significance in ClinVar (Variation ID: 36516). This variant is found in the African population with an allele frequency of 0.80% (199/24970 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 33 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Val33Leu variant is uncertain at this time.
Natera, Inc. RCV001276303 SCV001462434 benign Familial mediterranean fever, autosomal dominant 2020-06-06 no assertion criteria provided clinical testing

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