ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.1037-7T>A (rs61754381)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626672 SCV000747375 pathogenic Albinism; Nystagmus; Myopia 2017-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085889 SCV000228864 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515357 SCV000611334 pathogenic Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; Albinism, ocular, with sensorineural deafness; Skin/hair/eye pigmentation, variation in, 3 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000085889 SCV000321992 pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The c.1037-7T>A pathogenic variant in the TYR gene has been reported previously in both the compound heterozygous and apparently homozygous state in multiple individuals with oculocutaneous albinism type 1 (Goto et al., 2004; Hutton and Spritz, 2008; Ko et al., 2012; Wang et al, 2015). This variant is predicted to create a cryptic spice acceptor site and loss of the natural splice acceptor site in intron 2. An exon trapping system found that the c.1037-7T>A variant caused the insertion of 4 base pairs upstream of the common acceptor site for exon 3, resulting in a premature termination codon downstream from this variant (Goto et al., 2004). The c.1037-7T>A variant is observed in 159/10,108 (1.57%) alleles from individuals of Ashkenazi Jewish background, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.1037-7T>A as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000177050 SCV000249330 pathogenic Tyrosinase-negative oculocutaneous albinism 2015-02-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000287375 SCV000374873 pathogenic Oculocutaneous albinism 2017-04-27 criteria provided, single submitter clinical testing The TYR c.1037-7T>A splice-region variant has been reported in a total of 17 patients with oculocutaneous albinism (OCA), including three homozygotes, eleven compound heterozygotes, and three heterozygotes from a total of 264 affected Caucasian individuals (Hutton et al. 2008; Hutton et al. 2008; Gronskov et al. 2009; Gargiulo et al. 2011). Amongst individuals of Asian ancestry, this variant has been observed in cis with another intronic variant, c.1037-10delTT. This double variant has been reported in at least 13 affected individuals, including 11 compound heterozygotes and two heterozygotes, from a total of 194 affected Asian individuals (Goto et al. 2004; Wei et al. 2010; Ko et al. 2012; Lin et al. 2014; Wang et al. 2015). The c.1037-7T>A variant was absent from over 300 total controls, but is reported at a frequency of 0.00434 in the admixed American population of the 1000 Genomes Project. Using an in vitro assay in A375 cells, Goto et al. (2004) demonstrated that the c.1037-7T>A/c.1037-10delTT double variant causes abnormal splicing. Based on the evidence, the c.1037-7T>A 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 RCV000287375 SCV000966870 likely pathogenic Oculocutaneous albinism 2018-02-07 criteria provided, single submitter clinical testing The c.1037-7T>A (NM_000372.4) variant in TYR has been reported in at least 9 hom ozygous and 16 compound heterozygous individuals with oculocutaneous albinism ty pe 1 (OCA1) and segregated in an affected family member (Hutton 2008a, Hutton 2 008b, Gronskov 2009, Gargiulo 2011, Shahzad 2017, Fabos 2017, and Gao 2017). It has been reported as likely pathogenic or pathogenic in ClinVar (Variation ID#99 527) by multiple laboratories. This variant has been identified in 0.04% (49/126 ,124) of European chromosomes by the Genome Aggregation Database (gnomAD http:// gnomAD.broadinstitute.org; dbSNP rs61754381). This variant has also been identif ied in 1.5% (159/10108) of Ashkenazi chromosomes including 1 homozygote by the G enome Aggregation Database (gnomAD http://gnomAD.broadinstitute.org; dbSNP rs617 54381), which is consistent with some evidence suggesting it may be a founder mu tation in this population (Blumenfeld 2008, conference abstract: http://iovs.arv ojournals.org/article.aspx?articleid=2376752). This variant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are needed to fully establish its clinical significanc e, this variant is likely as pathogenic for OCA1 in an autosomal recessive manne r based upon multiple biallelic case observations and segregation in affected in dividuals. ACMG/AMP Criteria applied: PM3_VS, PS3_M.
Laboratory of Medical Genetics,National & Kapodistrian University of Athens RCV000789026 SCV000928362 pathogenic Oculocutaneous albinism type 1B 2018-05-10 criteria provided, single submitter clinical testing PS3,PS4,PM1
Retina International RCV000085889 SCV000118032 not provided not provided no assertion provided not provided
University of Washington Center for Mendelian Genomics,University of Washington RCV000755074 SCV000882892 likely pathogenic Nonsyndromic Oculocutaneous Albinism 2017-03-07 no assertion criteria provided research

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