rs794727836
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000143.4(FH):c.912_918delTTTTGTC(p.Phe305LeufsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P304P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000143.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.912_918delTTTTGTC | p.Phe305LeufsTer22 | frameshift_variant | Exon 7 of 10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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This frameshift variant alters the translational reading frame of the FH mRNA and causes the premature termination of FH protein synthesis. The variant has not been reported in individuals with FH-related diseases in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Phe305Leufs*22) 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 hereditary leiomyomatosis and renal cell cancer (PMID: 12772087). This variant is also known as 7-bp del at 782–788, P261 stop. ClinVar contains an entry for this variant (Variation ID: 198391). For these reasons, this variant has been classified as Pathogenic. -
Frameshift 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as c.782_788del, p.P261fs, p.P261X; This variant is associated with the following publications: (PMID: 12772087, 26447894, 15741255, 16597677) -
Hereditary leiomyomatosis and renal cell cancer Pathogenic:2
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Fumarase deficiency Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.912_918delTTTTGTC pathogenic mutation, located in coding exon 7 of the FH gene, results from a deletion of 7 nucleotides at nucleotide positions 912 to 918, causing a translational frameshift with a predicted alternate stop codon (p.F305Lfs*22). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at