ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1336G>A (p.Gly446Ser)

gnomAD frequency: 0.00011  dbSNP: rs104894317
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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) RCV000085920 SCV000338204 pathogenic not provided 2015-12-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000602413 SCV000731266 pathogenic Oculocutaneous albinism 2016-11-15 criteria provided, single submitter clinical testing The p.Gly446Ser variant in TYR has been reported in at least 9 compound heterozy gous individuals with oculocutaneous albinism type 1 (King 2003, Hutton 2008). T his variant has been identified in 3/66378 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894317) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency. In summary, th is variant meets criteria to be classified as pathogenic for oculocutaneous albi nism type 1 in an autosomal recessive manner based upon its occurrence in affect ed individuals and low frequency in control populations.
GeneDx RCV000085920 SCV000779693 pathogenic not provided 2024-09-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 28976636, 10987646, 1642278, 9259202, 13680365, 29345414, 31589614, 31980526, 21906913, 33808351, 18463683)
Labcorp Genetics (formerly Invitae), Labcorp RCV000085920 SCV001589665 pathogenic not provided 2024-12-31 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 446 of the TYR protein (p.Gly446Ser). This variant is present in population databases (rs104894317, gnomAD 0.01%). This missense change has been observed in individual(s) with albinism (PMID: 29345414). 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: 3801). 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 expected to disrupt TYR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000004005 SCV001821972 pathogenic Tyrosinase-negative oculocutaneous albinism 2021-07-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496250 SCV002814206 pathogenic Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN 2024-02-27 criteria provided, single submitter clinical testing
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust RCV003325937 SCV003853414 pathogenic Oculocutaneous albinism type 1B 2023-03-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085920 SCV004010111 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing TYR: PM3:Strong, PM1, PM2:Supporting, PP3, PP4, PS4:Supporting
Baylor Genetics RCV003466803 SCV004207548 pathogenic SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN 2024-03-23 criteria provided, single submitter clinical testing
OMIM RCV000004005 SCV000024171 pathogenic Tyrosinase-negative oculocutaneous albinism 1992-07-15 no assertion criteria provided literature only
Retina International RCV000085920 SCV000118063 not provided not provided no assertion provided not provided
PreventionGenetics, part of Exact Sciences RCV004540988 SCV004760635 pathogenic TYR-related disorder 2024-07-30 no assertion criteria provided clinical testing The TYR c.1336G>A variant is predicted to result in the amino acid substitution p.Gly446Ser. This variant has been reported many times along with a second pathogenic variant in TYR in individuals with oculocutaneous albinism (see for examples Tripathi et al. 1992. PubMed ID: 1642278; King et al. 2003. PubMed ID: 13680365; Marti et al. 2018. PubMed ID: 28976636). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3801). Given the evidence, we interpret this variant as pathogenic.

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