Submissions for variant NM_000143.4(FH):c.927G>A (p.Pro309=)

gnomAD frequency: 0.02428  dbSNP: rs61737760

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000179718	SCV000168542	benign	not specified	2012-05-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000131065	SCV000185995	benign	Hereditary cancer-predisposing syndrome	2014-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000179718	SCV000232010	benign	not specified	2014-12-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000179718	SCV000302645	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346503	SCV000356703	benign	Hereditary leiomyomatosis and renal cell cancer	2018-01-12	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	RCV000382481	SCV000356704	benign	Fumarase deficiency	2018-01-12	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	RCV000346503	SCV000356705	benign	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000589837	SCV000556450	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589837	SCV000695631	benign	not provided	2016-05-04	criteria provided, single submitter	clinical testing	Variant summary: The FH variant, c.927G>A (p.Pro309Pro) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico tools via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4203/120454 (1/28, 104 homozygotes), which exceeds the estimated maximum expected allele frequency for a pathogenic FH variant of 1/400000. In addition, multiple reputable clinical laboratories cite the variant as "benign." Therefore, the variant of interest is classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589837	SCV001159048	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000382481	SCV001750438	benign	Fumarase deficiency	2021-07-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000346503	SCV001750439	benign	Hereditary leiomyomatosis and renal cell cancer	2021-07-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000179718	SCV002552138	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000346503	SCV004015715	benign	Hereditary leiomyomatosis and renal cell cancer	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589837	SCV000802760	benign	not provided	2016-02-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000382481	SCV001457342	benign	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000179718	SCV001809037	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000179718	SCV001929846	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000179718	SCV001953572	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179718	SCV001970238	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000179718	SCV002035974	benign	not specified		no assertion criteria provided	clinical testing