ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.192G>T (p.Gln64His) (rs80338894)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153218 SCV000202692 pathogenic not provided 2013-11-22 criteria provided, single submitter clinical testing
Counsyl RCV000020126 SCV000485135 pathogenic Tyrosinemia type I 2015-12-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 64 of the FAH protein (p.Gln64His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 2 of the FAH coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs80338894, ExAC 0.05%). This variant has been reported as homozygous in individuals affected with tyrosinemia type I (PMID: 7942842, Invitae). ClinVar contains an entry for this variant (Variation ID: 21054). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change results in aberrant splicing (PMID: 7942842). 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
GeneReviews RCV000020126 SCV000040449 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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