Submissions for variant NM_000143.4(FH):c.556-4A>G

gnomAD frequency: 0.00004  dbSNP: rs370229813

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001569283	SCV000544268	uncertain significance	not provided	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the FH gene. It does not directly change the encoded amino acid sequence of the FH protein. This variant is present in population databases (rs370229813, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 405926). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001024280	SCV001186265	likely benign	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001569283	SCV001793327	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	Identified in an adolescent with bilateral pheochromocytoma who also harbored a missense variant in VHL, and tumor testing suggested there was at least partial loss of heterozygosity for the VHL variant (Lautenbach et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30761759)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268072	SCV002552144	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002489019	SCV002783440	uncertain significance	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2022-03-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001569283	SCV004218886	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	The FH c.556-4A>G variant has not been reported in individuals with FH-related conditions in the published literature. The frequency of this variant in the general population, 0.00017 (6/35146 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper FH mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000475091	SCV001458379	uncertain significance	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing