Submissions for variant NM_000143.4(FH):c.53C>T (p.Pro18Leu)

gnomAD frequency: 0.00597  dbSNP: rs201887750

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121088	SCV000168545	benign	not specified	2013-12-26	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.
Illumina Laboratory Services, Illumina	RCV000273634	SCV000356739	benign	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 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	RCV000331003	SCV000356740	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	RCV000331003	SCV000356741	likely benign	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000756164	SCV000556448	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000493989	SCV000581637	benign	Hereditary cancer-predisposing syndrome	2015-01-22	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756164	SCV000883890	likely benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121088	SCV000917376	benign	not specified	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: FH c.53C>T (p.Pro18Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 171230 control chromosomes, predominantly at a frequency of 0.021 within the African subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 8400-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FH causing Hereditary Leiomyomatosis and Renal Cell Cancer phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.53C>T in individuals affected with Hereditary Leiomyomatosis and Renal Cell Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121088	SCV002774701	benign	not specified	2021-07-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498563	SCV002806090	likely benign	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2021-10-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000331003	SCV004015720	benign	Hereditary leiomyomatosis and renal cell cancer	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121088	SCV004243535	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
ITMI	RCV000121088	SCV000085256	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000273634	SCV002085906	likely benign	Fumarase deficiency	2019-12-04	no assertion criteria provided	clinical testing