rs1126809

chr11-89284793-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM5 BP4_Strong BA1

The NM_000372.5(TYR):c.1205G>A(p.Arg402Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,610,930 control chromosomes in the GnomAD database, including 56,368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.18 (3239 hom., cov: 32)
  • Exomes 𝑓: 0.25 (53129 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:5 U:5 B:5 O:7
• Conservation: PhyloP100: 7.56

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000372.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029481053).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYR	NM_000372.5	c.1205G>A	p.Arg402Gln	missense_variant	4/5	ENST00000263321.6
TYR	XM_011542970.3	c.1205G>A	p.Arg402Gln	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.1205G>A	p.Arg402Gln	missense_variant	4/5	1	NM_000372.5	P1
TYR	ENST00000528243.1	n.203G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26853 AN: 151504 Hom.: 3237 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.176 AC: 44164 AN: 250300 Hom.: 5281 AF XY: 0.180 AC XY: 24365 AN XY: 135296

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0625

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.254 AC: 370235 AN: 1459308 Hom.: 53129 Cov.: 33 AF XY: 0.248 AC XY: 179800 AN XY: 726048

Gnomad4 AFR exome AF: 0.0410

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0686

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.177 AC: 26851 AN: 151622 Hom.: 3239 Cov.: 32 AF XY: 0.168 AC XY: 12473 AN XY: 74092

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.00156

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.186

Alfa AF: 0.259 Hom.: 3023

Bravo AF: 0.172

TwinsUK AF: 0.285 AC: 1058

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.0507 AC: 223

ESP6500EA AF: 0.281 AC: 2418

ExAC AF: 0.176 AC: 21389

Asia WGS AF: 0.0310 AC: 111 AN: 3478

EpiCase AF: 0.276

EpiControl AF: 0.273

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:5 Uncertain:5 Benign:5 Other:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:1 Other:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
other, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 24, 2021	DNA sequence analysis of the TYR gene demonstrated a sequence change, c.1205G>A, in exon 4 that results in an amino acid change, p.Arg402Gln. The p.Arg402Gln substitution is a well-documented temperature-sensitive reduced function allele that alone is not sufficient to cause an oculocutaneous albinism phenotype. However, the p.Arg402Gln substitution, if found in compound heterozygous state with a pathogenic mutation, may be associated with a mild oculocutaneous albinism type 1B (OCA1B) or ocular albinism (OA) phenotype (PMIDs: 7704033, 19938076, 18463683, 18326704, 23504663). The p.Arg402Gln substitution has been described in the gnomAD database with a high population frequency of 28% in the European American population (dbSNP rs1126809). Some studies have suggested that the p.Arg402Gln substitution is not associated with mild OCA1B or OA phenotype, due to its high frequency in the general population and the presence of this variant in trans with a pathogenic variant in unaffected parents (PMID: 19208379). It has been proposed that the p.Arg402Gln variant causes a partial albinism phenotype only when paired with certain genetic backgrounds (PMIDs: 7704033, 19938076) and multiple studies have shown that the p.Arg402Gln variant is more common in OCA patients with one TYR pathogenic variant than in patients with two pathogenic variants (PMIDs: 18463683, 18326704, 19938076, 23504663). Reduced function allele
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TYR: PM3:Very Strong, PM5, PM2:Supporting, BP4 -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Tyrosinase-negative oculocutaneous albinism Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 19, 2019	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP3,PP4,PP5,BA1. This variant was detected in homozygous state. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The variant TYR:c.1205G>A (p.Arg402Gln) was identified in dbSNP (ID: rs1126809) and ClinVar. The variant was identified in ClinVar with conflicting classifications (classified as pathogenic by OMIM, classified as likely pathogenic by the Centre for Mendelian Genomics, classified as uncertain significance by EGL Genetic Diagnostics, classified as likely benign by Illumina Clinical Services Laboratory, classified as benign by GeneReviews and PreventionGenetics). In one study, 122 patients had one pathogenic variant of the TYR gene and the p.Arg402Gln variant within a cohort of 268 patients diagnosed with oculocutaneous albinism type 1 (OCA1), emphasizing in favour of p.Arg402Gln being a mildly pathogenic TYR variant when associated in trans with another pathogenic variant (Monferme_2018_30472657). In another study, 2 patients in a cohort of 12 presenting with autosomal recessive ocular albinism (AROA) were each a compound heterozygote for a different pathologic mutant allele and an allele containing a ‘normal’ polymorphism, Arg402Gln. In these patients, AROA thus appears to represent a clinically mild form of OCA1 (Fukai_1995_7704033). Another study involving the clinical diagnosis of 30 Iranian OCA1 patients detected 6 patients with the heterozygous p.Arg402Gln variant, with two of those patients heterozygous for one other reported missense mutation in the TYR gene (Kalahroudi_2014_ 25216246). In another cohort with 18 probands categorized as having hypomorphic albinism, 6 had inherited the p.Arg402Gln variant in addition to another common TYR variant, p.Ser192Tyr (Norman_2017_28667292). The variant was identified in control databases in 49,703 of 281,606 chromosomes (5,932 homozygous) at a frequency of 17.6498%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 3501 of 128,366 chromosomes (freq: 4,795) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Arg402Gln residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Oculocutaneous albinism type 1B Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2023	Variant summary: TYR c.1205G>A (p.Arg402Gln) results in a conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.18 in 250300 control chromosomes in the gnomAD database, including 5281 presumably unaffected homozygotes. The observed variant frequency is approximately 32 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. Although widely reported in the literature due to its high population frequency, to our knowledge, no penetrant association of c.1205G>A in individuals affected with inherited autosomal recessive Oculocutaneous Albinism have been confirmed. There is evidence suggesting that c.1205G>A is acting as a hypomorphic variant, causing a mild form of albinism when in compound heterozygous state with a complete loss-of-function TYR change (example, Monferme_2019 cited in Michaud_2022). Homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82), although the 95% CI overlaps 1 (Michaud_2022). Per ACMG guidelines for the Interpretation of Sequence Variants, If the CI includes 1.0, there is little confidence in the assertion of association (Richards_2015). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant in isolation was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	This variant is very common in the general population, being documented in 27% of alleles in individuals of European (Non-Finnish) descent. 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.575C>A (p.Ser192Tyr), 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.1205G>A (p.Arg402Gln) variant is part of the complex allele or not, then the clinical significance of it is uncertain. -

Temperature-sensitive oculocutaneous albinism type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Albinism;C0600518:Choroidal neovascularization;C1848701:Elevated circulating hepatic transaminase concentration;C1853141:Slow decrease in visual acuity;C2673946:Foveal hypoplasia;C4021768:Abnormality of metabolism/homeostasis Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Oculocutaneous albinism type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 31, 2019

The TYR c.1205G>A p.(Arg402Gln) missense variant has been has been identified in individuals with a phenotype consistent oculocutaneous albinism (Monfermé et al. 2019; Chiang et al. 2009; Monferme et al. 2019). While this variant has been seen in affected individuals carrying two variants in TYR, it has also been seen in a compound heterozygous state in asymptomatic individuals (Chiang et al. 2009; Oetting et al. 2009; Monfermé et al. 2019). Furthermore, segregation studies have shown discrepant results, whereby some unaffected family members have the same genotype as affected individuals (Oetting et al. 2009). This variant has been reported at a frequency of 0.2728 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1) including many homozygotes. Despite the high frequency, this variant is suggested to be a hypomorphic allele with very reduced penetrance and highly variable expressivity, resulting in a milder form of oculocutaneous albinism (Chiang et al. 2009; Monfermé et al. 2019; Wang and Chiang 2019). It has also been suggested that additional modifiers may be playing a role in disease etiology (Wang and Chiang 2019). Functional studies have shown a temperature-sensitive effect of this variant in HeLa cells, whereby tyrosinase activity was reduced in cells that were transfected with p.(Arg402Gln variant plasmids compared to wild-type at 37 degrees Celsius, but not at 31 degrees Celsius. The authors suggest protein misfolding occurs in the presence of the variant (Tripathi et al. 1991). Similarly, experiments in cultured human melanocytes showed reduced enzyme activity and protein expression in homozygous variant melanocytes at 37 degrees Celsius. Protein expression was also decreased in skin samples. Immunofluorescence studies showed that variant protein was only localized in the endoplasmic reticulum, while wild-type was also present in dendrites, suggested occurrence of protein misfolding. Of note, melanin levels were not different between variant and wild-type melanocytes (Jagirdar et al. 2014). This variant is located near a copper binding domain and other missense variants observed in this region have been identified in patients (Oetting 2000). Based on the collective evidence, the c.1205G>A p.(Arg402Gln) variant is classified as a variant of uncertain significance for oculocutaneous albinism type 1. -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Melanoma, cutaneous malignant, susceptibility to, 8 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Skin/hair/eye pigmentation 3, blue/green eyes Other:1

association, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Autosomal recessive ocular albinism Other:1

other, no assertion criteria provided

clinical testing

Molecular Vision Laboratory

Sep 10, 2018

Autosomal recessive ocular albinism (AROA) has been linked to compound heterozygosity of TYR mutations with Arg402Gln. Arg402Gln has been shown to encode for a tyrosinase with reduced thermal stability suggesting a hypomorphic effect. The variant has reduced penetrance as there exists a discrepancy between expected incidence of Arg402Gln compound heterozygotes and AROA prevalence. Segregation studies have also revealed unaffected compound heterozygotes suggesting there are additional factors contributing to the AROA condition. Population allele frequency is high (gnomAD AF 0.19287) and there are unaffected homozygotes. hypomorphic allele

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

association, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.7e-7	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.029	D
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.16
MPC		0.066
ClinPred		0.017	T
GERP RS		4.7
Varity_R		0.57
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1126809; hg19: chr11-89017961; COSMIC: COSV54472906;