Submissions for variant NM_000243.3(MEFV):c.1260+10C>T

gnomAD frequency: 0.00035  dbSNP: rs104895137

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000668	SCV000052830	benign	not specified	2022-07-16	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1260+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 247282 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00057 vs 0.022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1260+10C>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign n=2, like benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000030170	SCV000753985	benign	Familial Mediterranean fever	2024-01-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000668	SCV001157698	likely benign	not specified	2019-05-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000030170	SCV001277729	uncertain significance	Familial Mediterranean fever	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001280974	SCV001468355	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2020-09-30	criteria provided, single submitter	clinical testing	MEFV NM_000243.2 exon 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV001705603	SCV001865495	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262578	SCV002543390	uncertain significance	Autoinflammatory syndrome	2021-08-09	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224107	SCV003920198	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 3 c.1260+10C>T: This variant has not been reported in the literature but is present in 0.9% (96/10270) of Ashkenazi Jewish alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299421-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:36498) and is also present in the InFevers database (https://infevers.umai-montpellier.fr/web/detail_mutation.php). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000030170	SCV000115774	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000030170	SCV002087409	likely benign	Familial Mediterranean fever	2020-05-13	no assertion criteria provided	clinical testing