Submissions for variant NM_000372.5(TYR):c.242C>T (p.Pro81Leu)

gnomAD frequency: 0.00018  dbSNP: rs28940876

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085939	SCV000224203	pathogenic	not provided	2015-04-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000085939	SCV000491312	pathogenic	not provided	2023-09-26	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: 10987646, 28451379, 1903591, 13680365, 18326704, 1970634, 31233279, 30609409, 31589614, 32581362, 33808351, 8434585, 37327787, 29345414, 34662886)
Genetic Services Laboratory, University of Chicago	RCV000003970	SCV000597783	pathogenic	Oculocutaneous albinism type 1A	2016-02-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599844	SCV000713082	pathogenic	Oculocutaneous albinism	2017-03-28	criteria provided, single submitter	clinical testing	The p.Pro81Leu (NM_000372.4 c.242C>T) variant in TYR has been reported in 4 hete rozygous, 1 homozygous and 7 compound heterozygous individuals with Oculocutaneo us albinism type 1 related disorders (OCA1) (Giebel 1990, King 2003, Opitz 2004, Hutton 2008, Rooryck 2008), segregated in at least 8 family members in 2 famili es (Giebel 2003), and has been reported at pathogenic in ClinVar (Variation ID#3 772). This variant has been identified in 0.015% (10/66458) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs28940876). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, this variant meets criteria to be classified as pathogenic for OCA 1 in an autosomal recessive manner based upon biallelic case observations and se gregation in affected individuals.
Ambry Genetics	RCV000623980	SCV000741319	pathogenic	Inborn genetic diseases	2023-10-03	criteria provided, single submitter	clinical testing	The c.242C>T (p.P81L) alteration is located in exon 1 (coding exon 1) of the TYR gene. This alteration results from a C to T substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.009% (26/282452) total alleles studied. The highest observed frequency was 0.017% (22/128894) of European (non-Finnish) alleles. This variant has been identified homozygous and likely in trans with a TYR second variant in multiple individuals diagnosed with oculocutaneous albinism (Hutton, 2008; Gao, 2017), as well as in a three individuals from a large family (Giebel, 1990). Another alteration at the same codon, c.241C>T (p.P81S), has been described in one individual with oculocutaneous albinism (King, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV001249700	SCV001423722	pathogenic	Oculocutaneous albinism type 1B	2019-10-31	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the TYR c.242C>T (p.Pro81Leu) missense variant has been identified a total of 31 individuals with oculocutaneous albinism type 1, including in three individuals in a homozygous state, in seven individuals in a compound heterozygous state, and in 14 individuals in an assumed compund heterozygous state (Oetting et al. 1991; Giebel et al. 1991; Hutton et al. 2008; King et al. 2013; Goa et al. 2017). The p.Pro81Leu variant was absent from 33 control subjects but is reported at a frequency of 0.000171 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the application of the ACMG criteria, the p.Pro81Leu variant is classified as pathogenic for oculocutaneous albinism type 1.
Genome-Nilou Lab	RCV000003970	SCV001821924	pathogenic	Oculocutaneous albinism type 1A	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085939	SCV002189499	pathogenic	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the TYR protein (p.Pro81Leu). This variant is present in population databases (rs28940876, gnomAD 0.02%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1970634, 8434585, 10987646, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3772). 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) indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000003970	SCV002519927	pathogenic	Oculocutaneous albinism type 1A	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496249	SCV002809417	pathogenic	Oculocutaneous albinism type 1A; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2021-11-04	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387499	SCV004099254	pathogenic	TYR-related disorder	2023-07-28	criteria provided, single submitter	clinical testing	PM2, PM3_VeryStrong, PP1, PP3
Baylor Genetics	RCV003466799	SCV004207536	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-14	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993735	SCV004812507	pathogenic	Oculocutaneous albinism type 1	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in TYR is predicted to replace proline with leucine at codon 81, p.(Pro81Leu). The proline residue is highly conserved (98/98 vertebrates, UCSC), and is located in the lumenal melanosome domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.02% (22/128,894 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is a commonly reported pathogenic variant and has been detected in multiple individuals with oculocutaneous albinism in the homozygous state and compound heterozygous with a second pathogenic variant in the gene (PMID: 8434585, 28451379). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP3.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003970	SCV005398934	pathogenic	Oculocutaneous albinism type 1A	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 26 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants in the TYR gene reported in individuals with OCA1 (PMIDs: 13680365, 18463683, 28451379). Homozygous individuals present with classic OCA1A phenotype (PMID: 1970634). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Homozygous individuals presented no pigment and no detectable tyrosine activity in anagen hairbulbs (PMID: 1970634). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003970	SCV000024135	pathogenic	Oculocutaneous albinism type 1A	1991-07-01	no assertion criteria provided	literature only
Retina International	RCV000085939	SCV000118082	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505170	SCV000598734	likely pathogenic	Albinism	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003387499	SCV005351459	pathogenic	TYR-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The TYR c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has been reported as a causative variant for oculocutaneous albinism (Giebel et al. 1990. PubMed ID: 1970634; Hutton and Spritz 2008. PubMed ID: 18463683; Ceyhan-Birsoy et al. 2019. PubMed ID: 30609409). This variant is reported in 0.017% 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/3772). Given all the evidence, we interpret this variant as pathogenic.