ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.242C>T (p.Pro81Leu) (rs28940876)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623980 SCV000741319 pathogenic Inborn genetic diseases 2016-02-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085939 SCV000224203 pathogenic not provided 2015-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000085939 SCV000491312 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The P81L variant in the TYR gene has been reported previously in the homozygous or compound heterozygous state in multiple unrelated individuals with oculocutaneous albinism (Giebel et al., 1990; Giebel et al., 1991; King et al., 2003; Gao et al., 2017). The P81L variant is observed in 19/126,402 alleles (0.015%) from individuals of non-Finnish European background, and 23/276,786 global alleles with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). The P81L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same codon (P81S) and nearby residues (R77W, R77G, R77Q, S79P, S79L, W80R, F84V, F84V) have been reported in the Human Gene Mutation Database in association with oculocutaneous albinism (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P81L as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000003970 SCV000597783 pathogenic Tyrosinase-negative oculocutaneous albinism 2016-02-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599844 SCV000713082 pathogenic Oculocutaneous albinism 2017-03-28 criteria provided, single submitter clinical testing 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505170 SCV000598734 likely pathogenic Albinism 2015-01-01 no assertion criteria provided research
OMIM RCV000003970 SCV000024135 pathogenic Tyrosinase-negative oculocutaneous albinism 1991-07-01 no assertion criteria provided literature only
Retina International RCV000085939 SCV000118082 not provided not provided no assertion provided not provided

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