Submissions for variant NM_000372.5(TYR):c.229C>T (p.Arg77Trp)

gnomAD frequency: 0.00006  dbSNP: rs61753184

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085933	SCV001770387	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9259202, 10987646, 13680365, 23504663, 28451379, 31077556, 28976636, 19865097, 34426522, 32552135, 33124154)
Genome-Nilou Lab	RCV000414815	SCV001821922	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085933	SCV002221234	pathogenic	not provided	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the TYR protein (p.Arg77Trp). This variant is present in population databases (rs61753184, gnomAD 0.008%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 9259202, 28976636, 31077556). ClinVar contains an entry for this variant (Variation ID: 99553). 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%. This variant disrupts the p.Arg77 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21985232, 31077556). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000414815	SCV002579975	pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467006	SCV004207612	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-30	criteria provided, single submitter	clinical testing
Retina International	RCV000085933	SCV000118076	not provided	not provided		no assertion provided	not provided
Baylor Genetics	RCV000414815	SCV000328778	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-05-15	no assertion criteria provided	clinical testing	This pathogenic variant has been previously described [PMID:9259202,23504663] and was found in trans with another pathogenic variant in TYR (NM_000372.4, c.229C>T) in an individual with autism, regression in language skills at 14mo of age, macrocephaly, joint laxity, atlantoaxial instability, fractures, delayed bone age, short stature, hip dysplasia, tyrosinase-negative oculocutaneous and cutaneous albinism and decrease pain sensitivity. A likely pathogenic de novo variant in TGFB2 (NM_003238.3, c.458G>A) was reported in the same individual. Heterozygotes for this variant are expected to be asymptomatic carriers.
PreventionGenetics, part of Exact Sciences	RCV004739349	SCV005349760	pathogenic	TYR-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The TYR c.229C>T variant is predicted to result in the amino acid substitution p.Arg77Trp. This variant has been reported in the compound heterozygous state in individuals with oculocutaneous albinism (Spritz et al. 1997. PubMed ID: 9259202; Marti et al. 2017. PubMed ID: 28976636; Zhong et al. 2019. PubMed ID: 31077556). This variant is reported in 0.0080% of alleles in individuals of African 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/99553/). Given the evidence, we interpret this variant as pathogenic.