Submissions for variant NM_000143.4(FH):c.1475_1476del (p.Leu492fs)

dbSNP: rs886041201

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000297629	SCV000329347	pathogenic	not provided	2016-09-29	criteria provided, single submitter	clinical testing	The c.1475_1476delTC variant in the FH gene has been reported previously in the heterozygous state in association with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Pithukpakorn et al., 2006). In lymphoblastoid cells and fibroblasts from an affected individual, FH enzyme activity was significantly reduced compared to controls (Pithukpakorn et al., 2006). This deletion causes a frameshift starting with codon Leucine 492, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Leu492HisfsX6. This variant is predicted to cause loss of normal protein function through protein truncation. Based on currently available evidence, we consider c.1475_1476delTC to be pathogenic.
Ambry Genetics	RCV000494455	SCV000581632	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-01	criteria provided, single submitter	clinical testing	The c.1475_1476delTC pathogenic mutation, located in coding exon 10 of the FH gene, results from a deletion of two nucleotides at nucleotide positions 1475 and 1476, causing a translational frameshift with a predicted alternate stop codon (p.L492Hfs*6). This alteration is expected to result in loss of function by premature protein truncation. This alteration has been observed in at least one individual who has a personal or family history that is consistent with FH-associated disease (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000297629	SCV000946284	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FH protein in which other variant(s) (p.Trp500*) have been determined to be pathogenic (PMID: 9635293, 21398687). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects FH function (PMID: 16597677). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 279807). This variant is also known as 1346_1347delTC. This premature translational stop signal has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (PMID: 16597677). This sequence change creates a premature translational stop signal (p.Leu492Hisfs*6) in the FH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the FH protein.
Myriad Genetics, Inc.	RCV003335299	SCV004043916	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-06-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV004567819	SCV005057742	pathogenic	Fumarase deficiency	2024-03-25	criteria provided, single submitter	clinical testing