ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1336G>A (p.Gly446Ser) (rs104894317)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085920 SCV000338204 pathogenic not provided 2015-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000085920 SCV000779693 likely pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The G446S variant in the TYR gene has been reported previously in association with oculocutaneous albinism type 1, and in one study was was identified in approximately 5.4% of 168 disease alleles among Caucasian individuals with oculocutaneous albinism type 1 (Tripathi et al., 1992; Spritz et al., 1997; Passmore et al., 1999; Hutton et al., 2008). The G446S variant is observed in 14/125870 (0.011%) alleles from individuals of non-Finnish European background and 15/275954 (0.005%) global alleles in large population cohorts, with no homozygotes identified (Lek et al., 2016). The G446S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants at the same residue (G446V) and nearby residues (S442P, D444G, D448N, Y449C, Y451C) have been reported in the Human Gene Mutation Database in association with oculocutaneous albinism type 1 (Liu et al., 2014; Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G446S as a likely pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000602413 SCV000731266 pathogenic Oculocutaneous albinism 2016-11-15 criteria provided, single submitter clinical testing The p.Gly446Ser variant in TYR has been reported in at least 9 compound heterozy gous individuals with oculocutaneous albinism type 1 (King 2003, Hutton 2008). T his variant has been identified in 3/66378 of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs104894317) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency. In summary, th is variant meets criteria to be classified as pathogenic for oculocutaneous albi nism type 1 in an autosomal recessive manner based upon its occurrence in affect ed individuals and low frequency in control populations.
OMIM RCV000004005 SCV000024171 pathogenic Tyrosinase-negative oculocutaneous albinism 1992-07-15 no assertion criteria provided literature only
Retina International RCV000085920 SCV000118063 not provided not provided no assertion provided not provided

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