chr1-241508781-G-T

Variant names:

• chr1-241508781-G-T
• rs398123166
• NM_000143.4:c.560C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000143.4(FH):​c.560C>A​(p.Ser187*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60
• Publications: 5 publications found

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]

FH Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241508781-G-T is Pathogenic according to our data. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-241508781-G-T is described in CliVar as Pathogenic. Clinvar id is 405935.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.560C>A	p.Ser187*	stop_gained	Exon 5 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.560C>A	p.Ser187*	stop_gained	Exon 5 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000396 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser187*) 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 variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 405935). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.6
Vest4		0.89
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 4

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

Other links and lift over

dbSNP: rs398123166; hg19: chr1-241672081;