ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.974C>T (p.Thr325Met)

dbSNP: rs770713168
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668164 SCV000792719 uncertain significance Tyrosinemia type I 2017-07-20 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000668164 SCV001424413 likely pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing
Invitae RCV000668164 SCV002217098 pathogenic Tyrosinemia type I 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 325 of the FAH protein (p.Thr325Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 12555948, 21752152, 25681080, 34023347; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552826). 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 FAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd RCV000668164 SCV003842246 likely pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing A Heterozygous Missense variant c.974C>T in Exon 12 of the FAH gene that results in the amino acid substitution p.Thr325Met was identified. The observed variant has a minor allele frequency of 0.00000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic, Likely Pathogenic, Uncertain Significance, and Conflicting Interpretations (variant ID: 552826). This variant has previously been reported for Tyrosinemia by Couce ML, et,al.,2011.Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Neuberg Centre For Genomic Medicine, NCGM RCV000668164 SCV004047832 pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing The missense variant c.974C>T(p.Thr325Met) variant has been observed in individuals affected with tyrosinemia type I (Heath et. al., 2002; Couce et. al., 2011; Angileri et. al., 2015). Advanced modeling of protein sequence and biophysical properties reported by a lab indicates that this missense variant is expected to disrupt FAH protein function. The p.Thr325Met variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Variant of Uncertain Significance (VUS). The amino acid change p.Thr325Met in FAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 325 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic
Baylor Genetics RCV000668164 SCV004195865 pathogenic Tyrosinemia type I 2023-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668164 SCV004223443 pathogenic Tyrosinemia type I 2023-11-01 criteria provided, single submitter clinical testing Variant summary: FAH c.974C>T (p.Thr325Met) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like_C-terminal (IPR005959) 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 4e-06 in 248514 control chromosomes. c.974C>T has been reported in the literature in multiple individuals affected with Tyrosinemia Type 1 (e.g. Couce_2011, Cheema_2020, Heath_2002, Hegarty_2021). 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: 33083013, 21752152, 12555948, 34023347). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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