rs1126809
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBA1
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
NM_000372.5 missense
Scores
6
4
8
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TYR | NM_000372.5 | c.1205G>A | p.Arg402Gln | missense_variant | 4/5 | ENST00000263321.6 | NP_000363.1 | |
| TYR | XM_011542970.3 | c.1205G>A | p.Arg402Gln | missense_variant | 4/6 | XP_011541272.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TYR | ENST00000263321.6 | c.1205G>A | p.Arg402Gln | missense_variant | 4/5 | 1 | NM_000372.5 | ENSP00000263321 | P1 | |
| TYR | ENST00000528243.1 | n.203G>A | non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes 0.177 AC: 26853AN: 151504Hom.: 3237 Cov.: 32
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GnomAD3 exomes AF: 0.176 AC: 44164AN: 250300Hom.: 5281 AF XY: 0.180 AC XY: 24365AN XY: 135296
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GnomAD4 exome AF: 0.254 AC: 370235AN: 1459308Hom.: 53129 Cov.: 33 AF XY: 0.248 AC XY: 179800AN XY: 726048
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GnomAD4 genome 0.177 AC: 26851AN: 151622Hom.: 3239 Cov.: 32 AF XY: 0.168 AC XY: 12473AN XY: 74092
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ClinVar
Significance: Conflicting classifications of pathogenicity; other
Submissions summary: Pathogenic:5Uncertain:6Benign:5Other:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Benign:1Other:2
| not provided, no classification provided | literature only | Retina International | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | TYR: PM3:Very Strong, PM5, PM2:Supporting, BP4 - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| 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 |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 24, 2017 | - - |
Tyrosinase-negative oculocutaneous albinism Uncertain:2Benign: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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| 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. - |
Oculocutaneous albinism type 1B Pathogenic:2Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2013 | - - |
| Likely pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
not specified Uncertain:1Benign: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. - |
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 | - - |
Temperature-sensitive oculocutaneous albinism type 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2013 | - - |
Albinism or congenital nystagmus Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | NHS Central & South Genomic Laboratory Hub | Jul 01, 2024 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
P
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at