Submissions for variant NM_000372.5(TYR):c.1264C>T (p.Arg422Trp)

gnomAD frequency: 0.00004  dbSNP: rs749979474

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001531121	SCV001746097	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531121	SCV001795713	likely pathogenic	not provided	2021-05-06	criteria provided, single submitter	clinical testing	Published functional studies have been inconsistent as to the effect of the R422W variant, with some studies showing only a slight decrease in enzyme activity and others showing no retained enzyme activity (Dolinska et al., 2014; Mondal et al., 2016; Dolinska et al., 2017; Farney et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 33177702, 32581362, 28976636, 28451379, 13680365, 30868138, 28667292, 27537549, 27775880, 24392141, 32898648)
Genome-Nilou Lab	RCV001591148	SCV001821969	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001591148	SCV002580135	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-05-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470633	SCV004207578	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001531121	SCV005835866	uncertain significance	not provided	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 422 of the TYR protein (p.Arg422Trp). This variant is present in population databases (rs749979474, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of TYR-related conditions (PMID: 13680365, 28667292, 28976636, 29345414, 32581362; Invitae). ClinVar contains an entry for this variant (Variation ID: 437987). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TYR function (PMID: 24392141, 27537549, 27775880). This variant disrupts the p.Arg422 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1900309, 31077556). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504932	SCV000598733	likely pathogenic	Albinism	2015-01-01	no assertion criteria provided	research