ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1265G>A (p.Arg422Gln)

gnomAD frequency: 0.00001  dbSNP: rs61754393
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085916 SCV001822231 pathogenic not provided 2024-12-20 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with decreased tyrosine hydroxylase, dopa oxidase, DHI oxidase, copper-binding and/or catalytic activities (PMID: 1900309, 9242509, 1429711); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1900309, 32552135, 10987646, 1900307, 1429711, 11284711, 9242509, 24392141, 27775880, 1943686, 18326704, 29437493, 31077556, 15146472, 2567165, 38145795, 36729443, 37605172, 34838614, 38542347)
Labcorp Genetics (formerly Invitae), Labcorp RCV000085916 SCV002232241 pathogenic not provided 2024-09-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 422 of the TYR protein (p.Arg422Gln). This variant is present in population databases (rs61754393, gnomAD 0.02%). This missense change has been observed in individual(s) with ocular albinism (PMID: 1900309, 31077556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3782). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TYR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TYR function (PMID: 1900309). For these reasons, this variant has been classified as Pathogenic.
Department of Medical Genetics, College of Basic Medicine, Army Medical University RCV003238721 SCV003935197 pathogenic Oculocutaneous albinism type 1B criteria provided, single submitter research
Baylor Genetics RCV003460415 SCV004207577 pathogenic SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN 2024-02-21 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004795371 SCV005418149 pathogenic Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B criteria provided, single submitter clinical testing PM2_Supporting+PM3_VeryStrong+PP4+PP3
OMIM RCV000003985 SCV000024151 pathogenic Temperature-sensitive oculocutaneous albinism type 1 1991-07-01 no assertion criteria provided literature only
Retina International RCV000085916 SCV000118059 not provided not provided no assertion provided not provided
PreventionGenetics, part of Exact Sciences RCV004739287 SCV005361862 pathogenic TYR-related disorder 2024-08-02 no assertion criteria provided clinical testing The TYR c.1265G>A variant is predicted to result in the amino acid substitution p.Arg422Gln. This variant has been reported in the compound heterozygous states in multiple individuals with oculocutaneous albinism (see for examples: Giebel et al. 1991. PubMed ID: 1900309; Zhong et al. 2019. PubMed ID: 31077556; Chuan et al. 2021. PubMed ID: 32552135). An alternate substitution of this amino acid (p.Arg422Trp) has also been reported in individuals with oculocutaneous albinism (King et al 2003. PubMed ID: 13680365). Functional studies have shown that the p.Arg422Gln substitution affects protein function (Toyofuku et al. 2001. PubMed ID: 11284711; Dolinska. 2014. PubMed ID: 24392141). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3782/). Given the evidence, we interpret this variant as pathogenic.

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