Submissions for variant NM_000372.5(TYR):c.915C>A (p.Asp305Glu)

gnomAD frequency: 0.00017  dbSNP: rs142170797

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486643	SCV000565644	uncertain significance	not provided	2021-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26764160, 13680365, 21906913, 19060277)
Fulgent Genetics, Fulgent Genetics	RCV000765023	SCV000896208	uncertain significance	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
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000789027	SCV000928363	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2018-05-10	criteria provided, single submitter	clinical testing	PS4,PM1,PP2,PP3
Illumina Laboratory Services, Illumina	RCV001109651	SCV001267012	uncertain significance	Oculocutaneous albinism	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000789027	SCV001821905	uncertain significance	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Invitae	RCV000486643	SCV002126395	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 305 of the TYR protein (p.Asp305Glu). This variant is present in population databases (rs142170797, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 13680365, 19060277, 27734839, 34008892). ClinVar contains an entry for this variant (Variation ID: 418532). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488627	SCV004241542	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: TYR c.915C>A (p.Asp305Glu) results in a conservative amino acid change located in the copper-binding domain (IPR002227) of 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 0.00034 in 1606724 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.0056), allowing no conclusion about variant significance. c.915C>A has been reported in the literature in compound heterozygous state together with a second pathogenic variant, in an affected individual (with dermatological abnormalities), however no further phenotype details were provided (Marinakis_2021). In addition, the variant was also reported in heterozygous state in individuals affected with Oculocutaneous Albinism in whom a second (likely) pathogenic mutation was not identified (e.g. King_2003, Gronskov_2009, Mauri_2016), and was also reported in unaffected controls (Hu_011, Dopazo_2016). These data do not allow any conclusion about variant significance. 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: 13680365, 19060277, 21906913, 27734839, 26764160, 34008892). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000486643	SCV004701771	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TYR: PM5, PM2:Supporting