chr11-89191214-C-T

Position:

chr11-89191214-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000372.5(TYR):c.832C>T(p.Arg278*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R278R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

TYR
NM_000372.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 0.910

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-89191214-C-T is Pathogenic according to our data. Variant chr11-89191214-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 99583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89191214-C-T is described in Lovd as [Pathogenic]. Variant chr11-89191214-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.832C>T	p.Arg278*	stop_gained	2/5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 linkuse as main transcript	c.832C>T	p.Arg278*	stop_gained	2/6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 linkuse as main transcript	c.832C>T	p.Arg278*	stop_gained	2/5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 linkuse as main transcript	n.893C>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251074

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461246

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

726928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000192

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg278*) in the TYR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663). This variant is present in population databases (rs62645904, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with oculocutaneous albinism (PMID: 23324268, 26165494, 27829221, 28266639). ClinVar contains an entry for this variant (Variation ID: 99583). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26252096, 16056219, 24721949, 32849781, 23324268, 22734612, 26165494, 15635296, 7902671, 27829221, 16767664, 28771251, 28266639, 16704458, 30487145, 30996339, 31199599, 31077556, 26689913, 10929771, 19865097, 33800529) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2017	- -

Tyrosinase-negative oculocutaneous albinism

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (48 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are more than 10 NMD-predicted variants that have been reported as likely pathogenic or pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with oculocutaneous albinism (ClinVar; PMIDs: 7902671; 11829136; 22734612; 31199599). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.832C>T (p.Arg278Ter) in TYR has been reported in many families and individuals affected with oculocutaneous albinism (Wang et al., 2016; Wei et al., 2015). The p.Arg278Ter variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in TYR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in TYR are known to be pathogenic (Simeonov et al., 2013). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099583, PMID:7902671, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000170, PM2_M). Each parent is heterozygous for the variant (PM3_P, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jun 19, 2018	The observed variant c.832C>T (p.Arg278Ter) is not reported in 1000 Genomes and its minor allele frequency in ExAC databases is 0.0002. The variant is found to be disease-causing by MutationTaster2. The reference codon is conserved across species. The observed variant has previously been reported in patients affected with oculocutaneous albinism (Wang et al., 2015) -

Oculocutaneous albinism

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2024	The p.Arg278X variant in TYR has been reported in the compound heterozygous or homozygous state in >10 individuals with oculocutaneous albinism (OCA). It was identified with other disease-causing variants in OCA, where the variants were confirmed in trans in at least 2 individuals (Wang 2016 PMID: 27829221, Shahzad 2017 PMID: 28266639, Arshad 2018, Lionel 2018 PMID: 28771251, Zhong 2019 PMID: 31077556, Shakil 2019 PMID: 30996339, Lin 2019 PMID: 31199599, Bibi 2020 PMID: 32849781). This variant segregated with OCA in > 4 affected relatives from 4 families (Wang 2016 PMID: 27829221, Arshad 2018, Shakil 2019 PMID: 30996339, Bibi 2020 PMID: 32849781). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 99583) and has been identified in 0.12% (106/91064) of South Asian chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org, v4.0.0), consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 278, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the TYR gene is an established disease mechanism in autosomal recessive oculocutaneous albinism. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive OCA. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2024	Variant summary: TYR c.832C>T (p.Arg278X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00019 in 251074 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00019 vs 0.0056), allowing no conclusion about variant significance. c.832C>T has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (example, Mondal_2012). 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. The following publication has been ascertained in the context of this evaluation (PMID: 23010199). ClinVar contains an entry for this variant (Variation ID: 99583). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	The TYR c.832C>T (p.Arg278Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg278Ter variant is a well-documented variant that has been reported in individuals with oculocutaneous albinism (OA) in multiple ethnic groups. Across a selection of the available literature, the p.Arg278Ter variant has been identified in 28 probands in a homozygous state, six probands in a compound heterozygous state, and three probands in a heterozygous state (Tripathi et al. 1993; Gershoni-Baruch et al. 1994; Goto et al. 2004; Sundaresan et al. 2004; Chaki et al. 2005; Renugadevi et al. 2010; Park et al. 2012; Wei et al. 2013; Wang et al. 2015). The p.Arg278Ter variant was absent from 137 control individuals and is reported at a frequency of 0.00115 in the South Asian population of the Exome Aggregation Consortium. Haplotype analysis suggested that p.Arg278Ter may be a founder variant (Chaki et al. 2005; Jaworek et al. 2012). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg278Ter 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. -

Oculocutaneous albinism type 1B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The stop-gained variant c.832C>T (p.Arg278Ter) in the TYR gene has been reported in the compound heterozygous and homozygous state in individuals affected with Oculocutaneous Albinism (Wei, Ai-Hua et al.,2015). This variant is reported with the allele frequency (0.01%) in the gnomAD Exome. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant the molecular diagnosis is not confirmed. -

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

Jun 09, 2024

- -

Nonsyndromic Oculocutaneous Albinism

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Mar 07, 2017

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism;CN028925:Ocular albinism with congenital sensorineural hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

TYR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The TYR c.832C>T variant is predicted to result in premature protein termination (p.Arg278*). This variant has been reported many times as causative for autosomal recessive oculocutaneous albinism (see for examples: Tripathi et al. 1993. PubMed ID: 7902671; Wang et al. 2015. PubMed ID: 2591901). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD, indicating it is relatively common in this population for a pathogenic variant. This is supported by a report that found this c.832C>T variant accounts for ~12% of causative TYR variants in a Chinese cohort of oculocutaneous albinism (Wei et al. 2010. PubMed ID: 19865097). Nonsense variants in TYR are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99583). Given the evidence, we interpret this variant as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Oculocutaneous albinism type 1B;C4551504:Tyrosinase-negative oculocutaneous albinism

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Oct 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.56

Vest4

0.94

GERP RS

2.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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