1-241517181-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000366560.4(FH):​c.267+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

FH
ENST00000366560.4 splice_donor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.17
Variant links:
Genes affected
FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08741031 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -20, new splice context is: gagGTgtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-241517181-C-T is Pathogenic according to our data. Variant chr1-241517181-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FHNM_000143.4 linkuse as main transcriptc.267+1G>A splice_donor_variant ENST00000366560.4 NP_000134.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkuse as main transcriptc.267+1G>A splice_donor_variant 1 NM_000143.4 ENSP00000355518 P1P07954-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 20, 2024This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 19, 2023This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 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). Disruption of this splice site has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (PMID: 16597677). It has also been observed to segregate with disease in related individuals. 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: 405927). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 24, 2022The c.267+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the FH gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will 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). The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is considered critical for protein function (Ambry internal data). Another alteration impacting the same donor site (c.267+1G>C) has been reported in multiple individuals with FH-associated disease (Wei MH et al. J Med Genet. 2006 Jan;43:18-27; Zhang L et al. Hum Mutat. 2020 01;41:103-109; Pithukpakorn M et al. J Med Genet. 2006 Sep;43:755-62). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
D
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.52
Position offset: 21
DS_DL_spliceai
1.0
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs878853691; hg19: chr1-241680481; API