Submissions for variant NM_000372.5(TYR):c.823G>T (p.Val275Phe)

gnomAD frequency: 0.00019  dbSNP: rs104894314

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192471	SCV000249343	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000085973	SCV000329587	pathogenic	not provided	2025-01-31	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: 18821858, 7886000, 23085273, 23504663, 34758253, 28976636, 8477259, 8217557, 9259202, 19208379, 12753405, 1903591, 20861488, 18463683, 27640074, 29345414, 28378818, 31719542, 31589614, 11295837, 1970634, 35894802, 38219857, 38523675)
Eurofins Ntd Llc (ga)	RCV000085973	SCV000332569	pathogenic	not provided	2016-12-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476919	SCV000893248	likely pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778348	SCV000914548	pathogenic	Oculocutaneous albinism	2018-08-14	criteria provided, single submitter	clinical testing	The TYR c.823G>T (p.Val275Phe) missense variant has been reported in at least three studies in which it is found in a total of 23 individuals with a clinical diagnosis of oculocutaneous albinism type 1 (OCA1) (of whom 20 are related), in a compound heterozygous state with either missense or frameshift variants on the second allele. The p.Val275Phe variant has also been found in a heterozygous state in one additional individual with a clinical diagnosis of OCA1 (Giebel et al. 1991; King et al. 2003; Hutton and Spritz 2008). Of the 23 affected compound heterozygous individuals, 19 were affected with OCA type 1B, and four were affected with OCA type 1A. The p.Val275Phe variant was also identified in a heterozygous state in an unspecified number of unaffected family members of one of the probands from Giebel et al. (1991). Quantitative assay of tyrosinase in freshly epilated anagen hairbulbs from one of the probands in Giebel et al. (1991) showed low activity at approximately 6% of normal range, and another showed no detectable activity. The variant was absent from 30 typically-pigmented controls (Giebel et al. 1991) but is reported at a frequency of 0.000206 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Val275Phe variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome-Nilou Lab	RCV000192471	SCV001821946	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085973	SCV002022496	pathogenic	not provided	2019-11-25	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000003972	SCV002061836	likely pathogenic	Oculocutaneous albinism type 1B	2021-04-26	criteria provided, single submitter	clinical testing	PP1, PP3, PS3_Moderate, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085973	SCV002150955	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 275 of the TYR protein (p.Val275Phe). This variant is present in population databases (rs104894314, gnomAD 0.02%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 1903591, 29345414). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3773). 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. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000192471	SCV002768530	pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with oculocutaneous albinism type IA (MIM#203100) and type IB (MIM#606952). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (28 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated tyrosinase functional domain (PDB, NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in more than ten patients with albinism or ocular albinism (ClinVar, PMID: 1903591; 18463683; 13680365). (SP) 0903 - This variant has limited evidence for segregation with disease. It has been shown to segregate with disease in at least one family (PMID: 1903591). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000778348	SCV003928953	pathogenic	Oculocutaneous albinism	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: TYR c.823G>T (p.Val275Phe) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250988 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (9.2e-05 vs 0.0056), allowing no conclusion about variant significance. c.823G>T has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (example: Lasseaux_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=9) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001542595	SCV004207546	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000003972	SCV000024137	pathogenic	Oculocutaneous albinism type 1B	2020-02-03	no assertion criteria provided	literature only
Retina International	RCV000085973	SCV000118116	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000085973	SCV001552023	pathogenic	not provided		no assertion criteria provided	clinical testing	The TYR p.V275F variant was identified in 1 homozygous and 14 compound heterozygous individuals with oculocutaneous albinism (Hutton_2008_PMID:18463683; Camand_2001_PMID:11295837; Giebel_1991_PMID:1903591). The variant was identified in dbSNP (ID: rs104894314) and ClinVar (classified as pathogenic by EGL Genetic Diagnostics, GeneDx, Illumina and Genetic Services Laboratory, University of Chicago, and as likely pathogenic by Fulgent Genetics). The variant was identified in control databases in 28 of 282378 chromosomes at a frequency of 0.00009916 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 28 of 128916 chromosomes (freq: 0.000217), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. Although the p.V275 residue is not conserved in mammals and other organisms, four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542595	SCV001760287	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532280	SCV004115086	pathogenic	TYR-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The TYR c.823G>T variant is predicted to result in the amino acid substitution p.Val275Phe. This variant has been reported in both the compound heterozygous and homozygous states in individuals with autosomal recessive oculocutaneous albinism (see for examples Giebel et al. 1991. PubMed ID: 1903591; King et al. 2003. PubMed ID: 13680365; Hutton et al. 2008. PubMed ID: 18463683). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) 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/3773/). Given the evidence, we interpret this variant as pathogenic.