chr1-241500572-A-G

Position:

chr1-241500572-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000366560.4(FH):c.1255T>C(p.Ser419Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,598,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S419A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FH
ENST00000366560.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.00

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]

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000366560.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-241500571-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 1-241500572-A-G is Pathogenic according to our data. Variant chr1-241500572-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92451.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
FH	NM_000143.4 linkuse as main transcript	c.1255T>C	p.Ser419Pro	missense_variant	9/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.1255T>C	p.Ser419Pro	missense_variant	9/10	1	NM_000143.4	ENSP00000355518	P1	P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00000685

AC:

AN:

145970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452482

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000685

AC:

AN:

145970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70652

show subpopulations

Gnomad4 AFR

AF:

0.0000254

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 419 of the FH protein (p.Ser419Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 15937070; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1126T>C (p.Ser376Pro). ClinVar contains an entry for this variant (Variation ID: 92451). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 16597677). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2024	PP3, PP4, PM2_moderate, PS4_moderate -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15937070, 31831373, 26945337]. Functional studies indicate this variant impacts protein function [PMID: 16597677]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2023	The p.S419P mutation (also known as c.1255T>C), located in coding exon 9 of the FH gene, results from a T to C substitution at nucleotide position 1255. The serine at codon 419 is replaced by proline, an amino acid with some similar properties. This alteration, also designated as S376P (1126T>C) in the literature, has been observed several individuals with a personal and/or family history that is consistent with HLRCC-related disease (Wei MH et al. J. Med. Genet. 2006 Jan;43(1):18-27; Sanz-Ortega J et al. Am J Surg Pathol. 2013 Jan;37:74-80; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

FH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The FH c.1255T>C variant is predicted to result in the amino acid substitution p.Ser419Pro. This variant is alternately referred to as p.Ser376Pro using Legacy nomenclature. This variant has been reported in individuals and families with hereditary leiomyomatosis and renal cell cancer (HLRCC; Table 1, Figure 3, Family 4400, Wei et al. 2006. PubMed ID: 15937070; Pithukpakorn et al. 2006. PubMed ID: 16597677; Lehtonen et al. 2011. PubMed ID: 21404119; Table 1, Sanz-Ortega et al. 2013. PubMed ID: 23211287; Table S1, Scharnitz et al. 2023. PubMed ID: 36777509). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/92451/). This variant is interpreted as pathogenic for autosomal dominant and recessive FH-associated disorders. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.47

Loss of MoRF binding (P = 0.0866);

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.94

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over