Submissions for variant NM_000372.5(TYR):c.140G>A (p.Gly47Asp)

gnomAD frequency: 0.00029  dbSNP: rs61753180

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085925	SCV000515217	pathogenic	not provided	2024-02-09	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: 18925668, 1642278, 28976636, 31589614, 33599182, 29345414, 8434585)
Genetic Services Laboratory, University of Chicago	RCV000003997	SCV000597781	pathogenic	Tyrosinase-negative oculocutaneous albinism	2016-12-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763287	SCV000893934	likely pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; Ocular albinism with congenital sensorineural hearing loss; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2018-10-31	criteria provided, single submitter	clinical testing
Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe	RCV000003997	SCV000998906	pathogenic	Tyrosinase-negative oculocutaneous albinism		criteria provided, single submitter	research
Ambry Genetics	RCV001267064	SCV001445245	pathogenic	Inborn genetic diseases	2018-02-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000003997	SCV001821919	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085925	SCV002229417	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 47 of the TYR protein (p.Gly47Asp). This variant is present in population databases (rs61753180, gnomAD 0.1%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1676041, 8128955, 8434585, 16417222, 19626598, 23242301, 23882993, 28976636). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Puerto Rican or Moroccan Jewish ancestry (PMID: 8128955, 8434585, 16417222, 23882993). ClinVar contains an entry for this variant (Variation ID: 3794). 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.Gly47 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 8434585, 26167114, 29345414), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460421	SCV004207551	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000003997	SCV000024163	pathogenic	Tyrosinase-negative oculocutaneous albinism	2008-11-15	no assertion criteria provided	literature only
OMIM	RCV000003998	SCV000024164	pathogenic	Oculocutaneous albinism type 1B	2008-11-15	no assertion criteria provided	literature only
Retina International	RCV000085925	SCV000118068	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004532284	SCV004114982	pathogenic	TYR-related disorder	2024-07-26	no assertion criteria provided	clinical testing	The TYR c.140G>A variant is predicted to result in the amino acid substitution p.Gly47Asp. This variant has been reported many times as causative for autosomal recessive oculocutaneous albinism (see for examples Oetting et al. 1993. PubMed ID: 8434585; Gershoni-Baruch et al. 1994. PubMed ID: 8128955; Camand et al. 2001. PubMed ID: 11295837; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.11% of alleles in individuals of Latino 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/3794). Given all the evidence, we interpret this variant as pathogenic.