11-89177979-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000372.5(TYR):āc.26T>Cā(p.Leu9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,082 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 Uncertain significance (ā ā ).
Frequency
Consequence
NM_000372.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: TYR c.26T>C (p.Leu9Pro) results in a non-conservative amino acid change in 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 251454 control chromosomes (gnomAD). c.26T>C has been reported in the literature in at least one compound heterozygous individual affected with Oculocutaneous Albinism (e.g., King_2003). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal tyrosine hydroxylase dopa oxidase activities, likely due to retention in the endoplasmic reticulum (e.g., Mondal_2016, Li_2022). The following publications have been ascertained in the context of this evaluation (PMID: 13680365, 35413289, 27537549). ClinVar contains an entry for this variant (Variation ID: 1338404). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 9 of the TYR protein (p.Leu9Pro). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with ocular albinism (PMID: 13680365). 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: 1338404). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYR protein function. Experimental studies have shown that this missense change affects TYR function (PMID: 27537549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at