rs121913121
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong
The NM_000143.4(FH):c.320A>C(p.Asn107Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,812 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. N107K) has been classified as Pathogenic.
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.320A>C | p.Asn107Thr | missense_variant | Exon 3 of 10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727206
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as N64T; This variant is associated with the following publications: (PMID: 16029320, 26900816, 21445611, 23211287, 21630274, 16757530, 19939761, 15937070, 12761039, 29909963, 11865300, 34604083, 36777509, 24625422) -
This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 107 of the FH protein (p.Asn107Thr). 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 (PMID: 11865300, 15937070, 16757530, 21630274, 23211287, 24625422, 26900816). It has also been observed to segregate with disease in related individuals. This variant is also known as c.191A>C, p.Asn64Thr. ClinVar contains an entry for this variant (Variation ID: 92455). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 11865300). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary leiomyomatosis and renal cell cancer Pathogenic:3
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12761039, 16237213, 11865300, 31831373, 34604083]. Functional studies indicate this variant impacts protein function [PMID: 16237213,11865300, 16597677, 20109171]. This variant is expected to disrupt protein structure [Myriad internal data]. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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The p.N107T pathogenic mutation (also known as c.320A>C), located in coding exon 3 of the FH gene, results from an A to C substitution at nucleotide position 320. The asparagine at codon 107 is replaced by threonine, an amino acid with similar properties. This alteration, designated as Asn64Thr or N64T, was identified in at least 12 apparently unrelated individuals from the UK who had multiple leiomyomata; in one of these families, the alteration segregated with disease in 16 affected relatives (Tomlinson I et al. Nat Genet. 2002 Apr;30(4):406-10; Alam N et al. Hum Mol Genet. 2003 Jun 1;12(11):1241-52). This alteration has been reported in additional individuals with cutaneous and/or uterine leiomyomas and/or renal cell carcinoma, some of whose tumors had loss of FH on immunohistochemical staining or FH loss-of-heterozygosity (Sanz-Ortega J et al. Am J Surg Pathol. 2013 Jan;37(1):74-80; Carvajal-Carmona L et al. J Clin Endocrinol Metab. 2006 Aug;91(8):3071-5; Wei M et al. J Med Genet. 2006 Jan;43(1):18-27; Udager AM et al. Am. J. Surg. Pathol. 2014 Apr;38:567-77; Trpkov K et al. Am. J. Surg. Pathol. 2016 Jul;40:865-75; Bardella C et al. J. Pathol. 2011 Sep;225:4-11). 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. -
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer Pathogenic:1
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Fumarase deficiency Pathogenic:1
Variant summary: FH c.320A>C (p.Asn107Thr) results in a non-conservative amino acid change located in the Fumarase/aspartase N-terminal domain (Fumarase/aspartase (N-terminal domain)) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.320A>C has been reported in the literature in multiple individuals affected with Autosomal dominant Leiomyomatosis and renal cell cancer (Tomlinson_2002, Carvajal-Carmona_2006, Wei_2006, Sanz-Ortega_2013, Udager_2014, Scharnitz_2023). 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: 16757530, 23211287, 36777509, 11865300, 26900816, 24625422, 15937070). ClinVar contains an entry for this variant (Variation ID: 92455). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at