Submissions for variant NM_000143.4(FH):c.1421C>G (p.Thr474Arg)

gnomAD frequency: 0.00004  dbSNP: rs369802820

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000381370	SCV000356658	benign	Hereditary leiomyomatosis and renal cell cancer	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000381370	SCV000356659	likely benign	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000332300	SCV000356660	uncertain significance	Fumarase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034487	SCV000544240	uncertain significance	not provided	2022-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 474 of the FH protein (p.Thr474Arg). This variant is present in population databases (rs369802820, gnomAD 0.2%). 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: 41585). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FH protein function. 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	RCV001011508	SCV001171835	likely benign	Hereditary cancer-predisposing syndrome	2020-10-05	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	RCV000034487	SCV002571586	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Observed in 1/572 individuals with atherosclerosis undergoing whole exome sequencing with no specific information about cancer history (PMID: 22703879); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36773955, 22703879)
Baylor Genetics	RCV000332300	SCV004197380	uncertain significance	Fumarase deficiency	2023-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000381370	SCV005404782	likely benign	Hereditary leiomyomatosis and renal cell cancer	2024-08-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034487	SCV000043259	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Natera, Inc.	RCV000332300	SCV001457336	uncertain significance	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004555533	SCV004765292	likely benign	FH-related disorder	2024-02-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).