ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1205G>A (p.Arg402Gln) (rs1126809)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000254054 SCV000303890 benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085910 SCV000340022 uncertain significance not provided 2017-10-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000379382 SCV000374872 likely benign Oculocutaneous albinism 2016-06-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000500466 SCV000597779 other Tyrosinase-negative oculocutaneous albinism 2020-01-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626673 SCV000747376 likely pathogenic Foveal hypoplasia; Albinism; Abnormality of metabolism/homeostasis; Elevated hepatic transaminases; Slow decrease in visual acuity; Choroidal neovascularization 2017-01-01 criteria provided, single submitter clinical testing
Mendelics RCV000500466 SCV001138404 likely benign Tyrosinase-negative oculocutaneous albinism 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000500466 SCV001370165 uncertain significance Tyrosinase-negative oculocutaneous albinism 2019-08-19 criteria provided, single submitter clinical testing 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.
Invitae RCV000085910 SCV001731474 benign not provided 2020-11-26 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000500466 SCV001821910 uncertain significance Tyrosinase-negative oculocutaneous albinism 2021-07-22 criteria provided, single submitter clinical testing
OMIM RCV000003978 SCV000024143 pathogenic Oculocutaneous albinism type 1B 2013-06-01 no assertion criteria provided literature only
OMIM RCV000003979 SCV000024145 pathogenic Oculocutaneous albinism type 1, temperature sensitive 2013-06-01 no assertion criteria provided literature only
OMIM RCV000003980 SCV000024146 risk factor Cutaneous malignant melanoma 8 2013-06-01 no assertion criteria provided literature only
OMIM RCV000003981 SCV000024147 association Skin/hair/eye pigmentation, variation in, 3 2013-06-01 no assertion criteria provided literature only
OMIM RCV000003982 SCV000024148 association Skin/hair/eye pigmentation 3, blue/green eyes 2013-06-01 no assertion criteria provided literature only
GeneReviews RCV000003978 SCV000086776 non-pathogenic Oculocutaneous albinism type 1B 2013-05-16 no assertion criteria provided curation Converted during submission to Benign.
Retina International RCV000085910 SCV000118053 not provided not provided no assertion provided not provided
Molecular Vision Laboratory RCV000721172 SCV000852087 other Autosomal recessive ocular albinism 2018-09-10 no assertion criteria provided clinical testing 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.
Center of Medical Genetics and Primary Health Care RCV001269379 SCV001448732 likely benign Malignant tumor of breast no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500466 SCV001551479 benign Tyrosinase-negative oculocutaneous albinism no assertion criteria provided clinical testing 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.

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