Submissions for variant NM_000372.5(TYR):c.865T>C (p.Cys289Arg)

gnomAD frequency: 0.00001  dbSNP: rs1468041471

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756679	SCV001986296	likely pathogenic	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Different missense changes at this residue and in nearby residues reported in the Human Gene Mutation database in association with oculocutaneous albinism, although evidence in support of pathogenicity is not available in some cases (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10671066, 10094567, 19338054, 23112997, 21749400, 25794181, 30868138, 34838614, 10987646, 33124154, 15146472)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001756679	SCV003441026	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 289 of the TYR protein (p.Cys289Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 10671066, 10987646). ClinVar contains an entry for this variant (Variation ID: 1303180). 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) performed at Invitae indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 80%. This variant disrupts the p.Cys289 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 13680365, 29345414), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237960	SCV005883904	pathogenic	Oculocutaneous albinism	2024-12-02	criteria provided, single submitter	clinical testing	Variant summary: TYR c.865T>C (p.Cys289Arg) results in a non-conservative amino acid change located in the Common central domain of tyrosinase (IPR002227) of 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 251240 control chromosomes. c.865T>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Oculocutaneous Albinism (Passmore_1999, Wei_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10671066, 10987646, 34838614). ClinVar contains an entry for this variant (Variation ID: 1303180). Based on the evidence outlined above, the variant was classified as pathogenic.