Submissions for variant NM_000550.3(TYRP1):c.208G>A (p.Ala70Thr)

gnomAD frequency: 0.00022  dbSNP: rs61752864

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000284548	SCV000477035	uncertain significance	Oculocutaneous albinism type 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001850933	SCV002147168	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 70 of the TYRP1 protein (p.Ala70Thr). This variant is present in population databases (rs61752864, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 28976636, 31719542). ClinVar contains an entry for this variant (Variation ID: 364852). 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 not expected to disrupt TYRP1 protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV002480252	SCV002797733	uncertain significance	Oculocutaneous albinism type 3; Skin/hair/eye pigmentation, variation in, 11	2021-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323525	SCV004028803	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: TYRP1 c.208G>A (p.Ala70Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 249952 control chromosomes. c.208G>A has been reported in the literature in individuals with clinical features of oculocutaneous albinism (examples: Campbell_2019, Marti_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Oculocutaneous albinism type 3. 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: 31719542, 28976636). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.