ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.192G>T (p.Gln64His)

gnomAD frequency: 0.00001  dbSNP: rs80338894
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000153218 SCV000202692 pathogenic not provided 2013-11-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020126 SCV000695443 pathogenic Tyrosinemia type I 2017-07-17 criteria provided, single submitter clinical testing Variant summary: The FAH c.192G>T (p.Gln64His) variant involves the alteration of a conserved nucleotide. This variant defies the donor-splice-site consensus sequence and it is considered a splice-site mutation (Ijaz_JPEM_2015). Human 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). 5/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts the loss of the SF2/ASF binding motif and the creation of a splice donor site. Functional studies showed decreased or absent FAH mRNA and protein levels in HT1 patients with this variant The variant of interest has been found in a large, broad control population, ExAC in 8/121410 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant has been reported in multiple HT1 patients, in both homozygotes and heterozygotes (with unknown secondary allele)( Rootwelt_AJHG_1994, Rootwelt_HM_1996, Ijaz_JPEM_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000020126 SCV000825982 pathogenic Tyrosinemia type I 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 64 of the FAH protein (p.Gln64His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338894, gnomAD 0.05%). This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 7942842; Invitae). ClinVar contains an entry for this variant (Variation ID: 21054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in retention of 94 nucleotides of intron 2 and introduces a premature termination codon (PMID: 7942842). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000020126 SCV000893379 pathogenic Tyrosinemia type I 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000020126 SCV001163399 pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000020126 SCV001194213 pathogenic Tyrosinemia type I 2019-12-09 criteria provided, single submitter clinical testing NM_000137.2(FAH):c.192G>T(Q64H) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 22975760, 23430822, 23193487, 14691918, 9101289 and 7942842. Classification of NM_000137.2(FAH):c.192G>T(Q64H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centogene AG - the Rare Disease Company RCV000020126 SCV001424412 pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing
3billion RCV000020126 SCV002058702 pathogenic Tyrosinemia type I 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021054, PS1_S). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product(PMID: 8829657, 7942842) (PS3_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (SPLICEAI: 0.9>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000060, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM RCV000020126 SCV004101494 likely pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing The missense variant c.192G>T(p.Gln64His) in FAH gene has been observed in individual(s) with tyrosinemia type I (Rootwelt H et.al.,1994). The amino acid Gln at position 64 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The p.Gln64His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.006009% is reported in gnomAD. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Gln64His in FAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic .
Neuberg Centre For Genomic Medicine, NCGM RCV003445079 SCV004171860 pathogenic T-substance anomaly criteria provided, single submitter clinical testing
GeneReviews RCV000020126 SCV000040449 not provided Tyrosinemia type I no assertion provided literature only Pakistani-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Natera, Inc. RCV000020126 SCV001461574 pathogenic Tyrosinemia type I 2020-09-16 no assertion criteria provided clinical testing

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