Submissions for variant NM_000372.5(TYR):c.575C>A (p.Ser192Tyr)

gnomAD frequency: 0.24593  dbSNP: rs1042602

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173114	SCV000224200	benign	not specified	2014-12-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000173114	SCV000303892	uncertain significance	not specified		criteria provided, single submitter	clinical testing	This variant is very common in the general population, being documented in 45% of alleles in individuals of Ashkenazi Jewish descent (http://gnomad.broadinstitute.org/variant/11-88911696-C-A). Given the high allele frequency, including thousands of homozygotes this variant is not considered pathogenic individually. However, when this variant is in cis (present in the same copy of TYR) with the variant c.1205G>A (p.Arg402Gln), there is strong evidence that they create a pathogenic allele. Functional and phenotypic studies of the complex allele (p.[Arg402Gln;Ser192Tyr]; commonly referred to as a haplotype in the literature) indicate that the two substitutions have a compound effect on thermal stability of the protein and phenotypic spectrum of the individual (Tripathi et al. 1991. PubMed ID: 1820207; Chaki et al. 2011. PubMed ID: 20861851; Jagirdar et al. 2014. PubMed ID: 24739399). The p.[Arg402Gln;Ser192Tyr] allele is thought to be a recombination of the two individual variant alleles and is reported in ~1-2% of alleles (Jagirdar et al. 2014. PubMed ID: 24739399; Norman et al. 2017. PubMed ID: 28667292). However, this complex allele is enriched (up to 20%) in OCA patients with only one previously identified pathogenic variant in TYR (Lasseaux et al. 2018. PubMed ID: 29345414; Grønskov et al. 2019. PubMed ID: 30679655; Campbell et al. 2019. PubMed ID: 31719542). Given the evidence, we interpret the p.[Arg402Gln;Ser192Tyr] allele as likely pathogenic. When it is unclear whether the c.575C>A (p.Ser192Tyr) variant is part of the complex allele or not, then the clinical significance of it is uncertain.
Illumina Laboratory Services, Illumina	RCV000341159	SCV000374871	benign	Oculocutaneous albinism	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Mendelics	RCV000055807	SCV001138402	benign	Tyrosinase-negative oculocutaneous albinism	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000085955	SCV001716936	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000055807	SCV001821902	benign	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085955	SCV002821656	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TYR: PM3:Very Strong, PM2, PP4, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173114	SCV003928952	likely benign	not specified	2023-04-07	criteria provided, single submitter	clinical testing	Variant summary: TYR c.575C>A (p.Ser192Tyr) 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 0.25 in 251456 control chromosomes in the gnomAD database, including 10823 homozygotes. The observed variant frequency is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYR causing Oculocutaneous Albinism phenotype (0.0056), strongly suggesting that the variant is benign. c.575C>A has been reported in the literature in individuals affected with Oculocutaneous Albinism and nystagmus without strong evidence of causality (Wei_2015, Thomas_2017). These reports do not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. At least two publications report experimental evidence evaluating an impact on protein function, showing ~60% of wildtype enzymatic activity and a reduction in pigment production in cells with the variant construct. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (four as benign, one as VUS, one as pathogenic, and one as association). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000003977	SCV000024142	association	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2017-10-30	no assertion criteria provided	literature only
GeneReviews	RCV000055807	SCV000086777	not provided	Tyrosinase-negative oculocutaneous albinism		no assertion provided	literature only
Retina International	RCV000085955	SCV000118098	not provided	not provided		no assertion provided	not provided
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000341159	SCV000777829	uncertain significance	Oculocutaneous albinism		no assertion criteria provided	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000055807	SCV001369187	uncertain significance	Tyrosinase-negative oculocutaneous albinism	2019-11-07	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PP3,PP4,BP6,BS1,BA1.