rs398123159
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000143.4(FH):c.1020T>A(p.Asn340Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,820 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N340N) has been classified as Likely benign.
Frequency
Consequence
NM_000143.4 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.1020T>A | p.Asn340Lys | missense_variant | 7/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.1020T>A | p.Asn340Lys | missense_variant | 7/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251316Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135824
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 19, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2021 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24684806, 21398687, 12772087, 23757202, 18366737, 28748451, 19939761, 28171700, 21445611, 24441663, 16597677, 26457356, 15937070, 31162287, 30741757) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 340 of the FH protein (p.Asn340Lys). This variant is present in population databases (rs398123159, gnomAD 0.003%). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087, 15937070, 26457356; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 891T>A (N297K, N297D). ClinVar contains an entry for this variant (Variation ID: 92447). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 30, 2022 | The FH c.1020T>A (p.Asn340Lys) variant (also known as 891T>A, N297K or N297D) has been reported in individuals with uterine fibroid/tumor (PMID: 30741757 (2019)) and HLRCC (PMIDs: 24441663 (2014), 16597677 (2006), 15937070 (2006), 12772087 (2003)). A cell line study indicated the variant caused significantly reduced FH enzyme activity in vitro (PMID: 16597677 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function also yielded predictions that this variant is damaging. The frequency of this variant in the general population, 0.000012 (3/251316 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary leiomyomatosis and renal cell cancer Pathogenic:3
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: 31831373, 31162287, 24441663, 15937070]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jan 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2023 | Variant summary: FH c.1020T>A (p.Asn340Lys) results in a non-conservative amino acid change located in the N-terminal Fumarate lyase domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251316 control chromosomes. c.1020T>A has been reported in the literature in multiple individuals affected with Hereditary Leiomyomatosis And Renal Cell Cancer (example, Kamihara_2021, Truong_2021, Forde_2020, Joseph_2015, Wei_FH_JMG_2006, Toro_FH_AJHG_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31831373, 26457356, 34994643, 12772087, 34654685, 15937070). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Fumarase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 02, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2023 | The p.N340K variant (also known as c.1020T>A), located in coding exon 7 of the FH gene, results from a T to A substitution at nucleotide position 1020. The asparagine at codon 340 is replaced by lysine, an amino acid with similar properties. This alteration, referred to as N297K or N297D in some literature, has been detected in multiple HLRCC families (Ambry internal data; Wei MH et al. J Med Genet. 2006 Jan;43(1):18-27; Toro JR et al. Am J Hum Genet. 2003 Jul;73(1):95-106; Picaud S et al. J Inherit Metab Dis. 2011 Jun;34(3):671-6). This alteration has also been reported as a pathogenic mutation in a 24 year old woman from a cohort of 2060 women with uterine smooth muscle tumors (Rabban JT et al. Am J Surg Pathol, 2019 05;43:639-655). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Further, based on internal structural analysis, this variant is anticipated to result in a decrease in protein function (Ambry Internal Data; Picaud S et al. J Inherit Metab Dis. 2011 Jun;34(3):671-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
FH-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 12, 2023 | The FH c.1020T>A variant is predicted to result in the amino acid substitution p.Asn340Lys. This variant has previously been reported to be causative for hereditary leiomyomatosis and renal cell cancer in several individuals (Toro et al. 2003. PubMed ID: 12772087, HGMD/ClinVar listed as T891A; Wei et al. 2006. PubMed ID: 15937070, reported as c.891T>A (N297K); Joseph et al. 2015. PubMed ID: 26457356, reported as c.1020T>A, p.N340K; Rabban JT et al 2019. PubMed ID: 30741757). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-241667430-A-T) and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/92447/?new_evidence=true). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at