Submissions for variant NM_000372.5(TYR):c.547G>A (p.Val183Met)

dbSNP: rs141930049

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001990234	SCV002256704	pathogenic	not provided	2022-09-20	criteria provided, single submitter	clinical testing	This variant disrupts the p.Val183 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 29345414), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 1465246). This missense change has been observed in individual(s) with oculocutaneous albinism (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs141930049, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 183 of the TYR protein (p.Val183Met). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004538695	SCV004121358	uncertain significance	TYR-related disorder	2023-07-06	criteria provided, single submitter	clinical testing	The TYR c.547G>A variant is predicted to result in the amino acid substitution p.Val183Met. To our knowledge, this variant has not been reported in the literature. However, a different variant affecting this same amino acid residue (p.Val183Leu) has been reported in the compound heterozygous state in an individual with oculocutaneous albinism (Supplementary Table 1 in Lasseaux et al. 2018. PubMed ID: 29345414). Additionally, here at PreventionGenetics, we have observed this c.547G>A (p.Val183Met) variant along with a frameshift variant in at least two individuals with oculocutaneous albinism (internal data). This variant is documented in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88911668-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699597	SCV005204208	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: TYR c.547G>A (p.Val183Met) results in a conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251442 control chromosomes. c.547G>A has been reported in the literature in compound heterozygous individuals affected with Oculocutaneous Albinism (Wei_2022, Loftus_2023). These data indicate that the variant may 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: 34838614, 37327787). ClinVar contains an entry for this variant (Variation ID: 1465246). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.