Submissions for variant NM_000143.4(FH):c.301C>T (p.Arg101Ter)

gnomAD frequency: 0.00001  dbSNP: rs121913120

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130873	SCV000185776	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The p.R101* pathogenic mutation (also known as c.301C>T), located in coding exon 3 of the FH gene, results from a C to T substitution at nucleotide position 301. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been identified in several individuals diagnosed with multiple leiomyomas, some of whom also had uterine fibroids and/or renal tumors (Tomlinson IP et al. Nat. Genet. 2002 Apr;30:406-10; Wei MH et al. J. Med. Genet. 2006 Jan;43:18-27; Gardie B et al. J. Med. Genet. 2011 Apr;48:226-34). One functional study showed significantly reduced FH enzyme activity in lymphoblastoid and fibroblast cell lines from a hereditary leiomyomatosis and renal cell cancer (HLRCC) patient with this mutation when compared to controls (Pithukpakorn M et al. J. Med. Genet. 2006 Sep;43:755-62). Of note, this alteration is also designated as R58X (c.172C>T) in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000199330	SCV000251440	pathogenic	not provided	2022-03-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: reduced enzymatic activity (Pithukpakorn 2006); Not observed in large population cohorts (gnomAD); Also known as R58X; This variant is associated with the following publications: (PMID: 21398687, 25525159, 16597677, 11865300, 25923021, 12761039, 15987702, 15937070, 28300276, 27635946, 28152038, 34426522)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000017619	SCV000537225	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2017-01-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515176	SCV000611195	pathogenic	Fumarase deficiency	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199330	SCV000632453	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg101*) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with renal cancer and uterine leiomyomas (PMID: 11865300, 15937070, 20549362, 25923021). This variant is also known as p.Arg58*. ClinVar contains an entry for this variant (Variation ID: 16232). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000199330	SCV001247137	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000199330	SCV002022981	pathogenic	not provided	2019-02-19	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000017619	SCV002556993	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2021-06-28	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000017619	SCV003936826	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg101*) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with renal cancer and uterine leiomyomas (PMID: 121398687, 25525159, 16597677, 11865300, 25923021, 12761039, 15987702, 15937070, 28300276, 27635946, 28152038, 34426522). This variant is also known as p.Arg58*. ClinVar contains an entry for this variant (Variation ID: 16232). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000017619	SCV004187886	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000515176	SCV004197332	pathogenic	Fumarase deficiency	2024-02-23	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000199330	SCV005197935	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing
OMIM	RCV000017619	SCV000037892	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2006-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000515176	SCV002085883	pathogenic	Fumarase deficiency	2020-11-25	no assertion criteria provided	clinical testing