ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1217C>T (p.Pro406Leu) (rs104894313)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623187 SCV000741318 pathogenic Inborn genetic diseases 2014-08-29 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 RCV000085913 SCV000700794 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000500113 SCV000897703 pathogenic Tyrosinase-negative oculocutaneous albinism 2019-02-27 criteria provided, single submitter clinical testing The observed variant NM_000372.4 :c.1217C>T (p.Pro406Leu) is a missense variation found in exon 4 of the TYR gene. It is a known pathogenic variant and has been reported in the ExAC and gnomAD database with an allele frequency of 0.003489 and 0.003845, respectively. The in silico prediction of this variant is disease causing by MutationTaster2. The proband's parents are heterozygous carriers of the following mutations in the TYR gene: c.1147G>A (p.Asp383Asn) in exon 3 and c.1217C>T (p.pro406leu) in exon 4. As the parents are phenotypically normal, it is likely that these mutations are in a cis arrangement. The proband thus has both of the parent's mutations in trans with a third variant c.1110G>A, which is de novo. In summary, the variant meets the ACMG criteria to be classified as pathogenic based upon the evidence stated above.
Fulgent Genetics,Fulgent Genetics RCV000762872 SCV000893252 likely pathogenic Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; Albinism, ocular, with sensorineural deafness; Skin/hair/eye pigmentation, variation in, 3 2018-10-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000500113 SCV000597799 likely pathogenic Tyrosinase-negative oculocutaneous albinism 2017-05-24 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000003976 SCV000845358 likely pathogenic Oculocutaneous albinism type 1B 2018-08-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000400442 SCV000374875 pathogenic Oculocutaneous albinism 2017-08-24 criteria provided, single submitter clinical testing The TYR c.1217C>T (p.Pro406Leu) missense variant has been reported in five studies in which it is found in at least 25 patients with oculocutaneous albinism (OCA) including in 13 patients in a homozygous state, four patients in a compound heterozygous state, two patients in a heterozygous state, and six individuals whose zygosity was not reported (Giebel et al. 1991; Hutton et al. 2008; Gargiulo et al. 2011; Jaworek et al. 2012; Ghodsinejad Kalahroudi et al. 2014). When clinical subtypes were described, the majority of affected individuals were reported to have OCA type 1. The variant was also detected in nine unaffected heterozygous carriers (Giebel LB et al. 1991). Khordadpoor-Deilamani et al. (2016) additionally found one patient with the p.Pro406Leu variant in a heterozygous state who also carried a homozugous frameshift variant in the SLC45A2 gene. The p.Pro406Leu variant was absent from at least 372 control chromosomes but is reported at a frequency of 0.00696 in the European population of the 1000 Genomes Project. Giebel et al. (1991) demonstrated that the tyrosinase activity in HeLa cells transfected with the p.Pro406Leu variant had only 7% of the activity of wild type. Toyofuku et al. (2001) expressed the p.Pro406Leu variant in COS7 cells and demonstrated that the variant protein is mislocalized, is more sensitive to endoglycosidase H digestion, and degrades more rapidly than wild type protein. Based on the collective evidence, the p.Pro406Leu variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000400442 SCV000712802 likely pathogenic Oculocutaneous albinism 2017-01-24 criteria provided, single submitter clinical testing The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at l east 5 homozygous and 7 compound heterozygous individuals with clinical features of Oculocutaneous albinism type 1 (OCA type 1), and segregated with disease in 3 affected relatives from 1 family (Giebel 1991, Hutton 2008, Council 2009, Wei 2010, Hu 2011, Gargiulo 2011, Kalahroudi 2014, Rooryck 2008, Gronskov 2009, and Jaworek 2011). This variant has been identified in 1% (275/25738) of Finnish chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitut e.org; dbSNP rs104894313, rs62645921). This variant has also been reported in Cl inVar (Variation ID#3777) as pathogenic or likely pathogenic. In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (Tripathi 1992, Spritz 1997, and Toyofuku 2001). It should be noted that so me studies have indicated that the pseudogene harbors this same variant. In summ ary, although additional studies are required to fully establish its significanc e, this variant is likely pathogenic for OCA type 1 in an autosomal recessive ma nner based upon case observations, segregation studies and in vitro data. ACMG/A MP Criteria applied: PM3 (upgraded to strong based on multiple occurences), PP1, PP3, PP5 (Richards 2015). Although the variant has been confirmed to occur in t he functional copy of the gene in this individual, we cannot guarantee that the evidence in the literature was based on observations in the functional gene. Ple ase note that, due to the technical limitations of the next generation sequencin g and Sanger confirmation assays, the TYR pseudogene cannot be reliably avoided. Therefore, before making clinical decisions regarding this variant, further tes ting via targeted assays that guarantee avoidance of TYR pseudogene would be req uired to confirm the presence of this variant.
OMIM RCV000003976 SCV000024141 pathogenic Oculocutaneous albinism type 1B 1992-07-15 no assertion criteria provided literature only
Retina International RCV000085913 SCV000118056 not provided not provided no assertion provided not provided

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