rs28940876

Positions:

chr11-89178195-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000372.5(TYR):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 7.48

Variant links:

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR links:

TYR (HGNC:):

TYR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89178194-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 11-89178195-C-T is Pathogenic according to our data. Variant chr11-89178195-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178195-C-T is described in Lovd as [Pathogenic]. Variant chr11-89178195-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-89178195-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 linkuse as main transcript	n.303C>T		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251066

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000321

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 03, 2016	- -

not provided

Pathogenic:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

TYR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 28, 2023	PM2, PM3_VeryStrong, PP1, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 03, 2024	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. -

Oculocutaneous albinism type 1B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 31, 2019

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. -

Oculocutaneous albinism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2017

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. -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

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. -

Albinism

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2024

- -

Oculocutaneous albinism type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.3

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.99

MPC

0.075

ClinPred

1.0

GERP RS

6.1

Varity_R

0.85

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over