rs28940876

chr11-89178195-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000372.5
• 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 ClinVar as [Pathogenic]. Clinvar id is 2679408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
TYR	NM_000372.5	c.242C>T	p.Pro81Leu	missense_variant	1/5	ENST00000263321.6
TYR	XM_011542970.3	c.242C>T	p.Pro81Leu	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.242C>T	p.Pro81Leu	missense_variant	1/5	1	NM_000372.5	P1
TYR	ENST00000526139.1	n.303C>T		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152192 Hom.: 0 Cov.: 32

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: 21 AN: 251066 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135704

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.: 0 Cov.: 30 AF XY: 0.000201 AC XY: 146 AN XY: 727216

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: 24 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74352

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.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 03, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1991	- -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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) -

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

- -

TYR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jul 28, 2023

PM2, PM3_VeryStrong, PP1, PP3 -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

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	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.99
MPC		0.075
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs28940876; hg19: chr11-88911363;