Submissions for variant NM_000372.5(TYR):c.1063G>C (p.Ala355Pro)

gnomAD frequency: 0.00005  dbSNP: rs62645908

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000085890	SCV001248573	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	TYR: PM3:Strong, PM1, PM2, PM5:Supporting, PP4
GeneDx	RCV000085890	SCV001801026	likely pathogenic	not provided	2024-11-21	criteria provided, single submitter	clinical testing	Identified in patients with features of oculocutaneous albinism in published literature (PMID: 9259202, 16170149); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30868138, 16170149, 34897530, 18463683, 27734839, 27959697, 9259202, 23504663, 15146472, 10987646)
Genome-Nilou Lab	RCV001588915	SCV001821960	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085890	SCV003440310	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the TYR protein (p.Ala355Pro). This variant is present in population databases (rs62645908, gnomAD 0.006%). This missense change has been observed in individual(s) with oculocutaneous albinism, however, it has frequently been observed on the same chromosome as c.1217C>T (p.Pro406Leu) (PMID: 9259202, 10987646, 15146472). ClinVar contains an entry for this variant (Variation ID: 99528). 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) has been performed 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. This variant disrupts the p.Ala355 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23504663, 27734839, 27959697). 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.
Baylor Genetics	RCV003460774	SCV004207581	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2023-08-27	criteria provided, single submitter	clinical testing
NHS Central & South Genomic Laboratory Hub	RCV004998225	SCV005393914	uncertain significance	Albinism; Congenital nystagmus	2024-11-11	criteria provided, single submitter	clinical testing	Identified an index case with likely oculo-cutaneous albinism, where the A335P variant was also detected with both the known pathogenic variant P406L and another pathogenic variant (phase testing has not been undertaken). Evidence for PM3 has only been included in our classification where the A335P variant was not identified in conjunction with P406L, owing to the genotype of our index case, co-occurrence evidence from GnomAD, and reports in the literature that A335P and P406L have been identified in cis (PMIDs: 10987646 and 34897530).
Retina International	RCV000085890	SCV000118033	not provided	not provided		no assertion provided	not provided
MGZ Medical Genetics Center	RCV001588915	SCV002579234	uncertain significance	Tyrosinase-negative oculocutaneous albinism	2021-07-09	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529898	SCV004117310	likely pathogenic	TYR-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The TYR c.1063G>C variant is predicted to result in the amino acid substitution p.Ala355Pro. This variant has been reported in the compound heterozygous state in individuals with oculocutaneous albinism (Spritz et al. 1997. PubMed ID: 9259202; Hovnik et al. 2021. PubMed ID: 34897530). Alternate substitutions of this same amino acid residue (p.Ala355Val and p.Ala355Glu) have also been reported in individuals with oculocutaneous albinism (reviewed in Table S1 in Simeonov et al. 2013. PubMed ID: 23504663). This c.1063G>C (p.Ala355Pro) variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic.