rs1060500901
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000143.4(FH):c.738+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000143.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.738+2T>C | splice_donor_variant, intron_variant | Intron 5 of 9 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Canonical splice site variant predicted to result in an in-frame deletion of a critical region [Exon 5 with multiple PATH missense variants and the substrate binding region]; Not observed in large population cohorts (Lek et al., 2016) -
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 405921). Disruption of this splice site has been observed in individuals with multiple cutaneous leiomyomas and/or renal cell carcinoma (PMID: 26173633, 28300276; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the FH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). -
Fumarase deficiency Pathogenic:1
Variant summary: FH c.738+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245936 control chromosomes. To our knowledge, no occurrence of c.738+2T>C in individuals affected with Hereditary Leiomyomatosis and Renal Cell Cancer and no experimental evidence demonstrating its impact on protein function have been reported. However, a different change at the same nucleotide (c.738+2T>A) has been reported in a patient affected with multiple cutaneous leiomyomas. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.738+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 5 in the FH gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with FH-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at