ClinVar Genomic variation as it relates to human health

This sequence change falls in intron 2 of the TYR gene. It does not directly change the encoded amino acid sequence of the TYR protein. This variant is present in population databases (rs61754381, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with oculocutaneous albinism (OCA) (PMID: 9163730, 13680365, 18463683, 19626598, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS2-7T>A. ClinVar contains an entry for this variant (Variation ID: 99527). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

PS3,PS4,PM1

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.

PM1, PM2, PP2, PP4, PP5

The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 15381243, 18463683, 22294196, 25919014, 28629449, 24721949, 18326704, PM3_S). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.95>=0.8, PP3_P). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099527). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000861, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The splice region variant c.1037-7T>A in TYR (NM_000372.5) has been reported to ClinVar as Pathogenic/Likely Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts. The c.1037-7T>A in TYR (NM_000372.5) has an allele frequency of 0.015 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.1037-7T>A 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 (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).

Variant summary: TYR c.1037-7T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site and one predicts the variant weakens the 3' acceptor site. Four predict the variant creates a new 3' acceptor site upstream from the canonical splice site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing by generating an abnormal splicing site, resulting in the insertion of 4 nucleotides which creates a premature termination codon downstream (e.g. Goto_2004). The variant allele was found at a frequency of 0.00095 in 249548 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00095 vs 0.0056), allowing no conclusion about variant significance. c.1037-7T>A has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Oculocutaneous Albinism (e.g. Goto_2004, Lasseaux_2018). These data indicate that the variant is very likely to be associated with disease. Twenty-one submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=19)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

The TYR c.1037-7T>A splice-region variant has been previously reported in a total of 17 patients with oculocutaneous albinism ( Hutton et al, 2008). Using an in vitro assay in A375 cells, it was observed that the c.1037-7T>A/c.1037-10delTT double variant causes abnormal splicing ( Goto et al, 2004 ). The c.1037-7T>A variant is observed in 153/10,040 (1.5239%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exomes. The nucleotide c.1037-7T>A in TYR is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

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.

The homozygous c.1037-7T>A variant identified in the TYR gene is a non-canonical splice site variant at the -7 position within intron 2/4. In silico algorithm SpliceAI predicts this variant to lead to the gain of a splice acceptor site 2bp downstream of the variant (Delta score 0.95), and the Transcript inferred Pathogenicity Score (TraP) is 0.519, which is >99% score-percentile, suggesting it is probably damaging to splicing. This variant is reported by multiple independent labs in ClinVar as Pathogenic or Likely Pathogenic (VarID:99527), and it has been reported in multiple affected individuals in the literature in both homozygous state [PMID:28629449, 28266639, others], and in compound heterozygosity with a second variant in TYR [PMID:13680365, 18326704, 19060277, others]. Given its presence in many affected individuals in the literature and in silico prediction of a damaging effect on splicing the homozygous c.1037-7T>A variant identified in the TYR gene is reported as Pathogenic.

ACMG categories: PS1,PM1,PM3,PP3,PP5

The homozygous c.1037-7T>A variant identified in the TYR gene is a non-canonical splice site variant at the -7 position within intron 2/4. In silico algorithm SpliceAI predicts this variant to lead to the gain of a splice acceptor site 2bp downstream of the variant (Delta score 0.95), and the Transcript inferred Pathogenicity Score (TraP) is 0.519, which is >99% score-percentile, suggesting it is probably damaging to splicing. This variant is reported by multiple independent labs in ClinVar as Pathogenic or Likely Pathogenic (VarID:99527), and it has been reported in multiple affected individuals in the literature in both homozygous state [PMID:28629449, 28266639, others], and in compound heterozygosity with a second variant in TYR [PMID:13680365, 18326704, 19060277, others]. Given its presence in many affected individuals in the literature and in silico prediction of a damaging effect on splicing the homozygous c.1037-7T>A variant identified in the TYR gene is reported as Pathogenic.

In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18326704, 13680365, 22294196, 26474496, 28451379, 28266639, 32411182, 8217557, 25525159, 11041370, 25919014, 18463683, 15381243, 28629449, 19060277, 19865097, 20861488, 24721949, 28555837, 30609409, 30868578, 31077556, 28976636, 30996339, 31229681, 31980526, 36964972, 36460718, 37217489, 34426522, 31589614, 10559577, 34008892, 33223529, 33808351, Moon[case report], 35328057, 34838614, 35923705, 33834455, 35052368, 34697415, 32552135)

NG_008748.1(NM_000372.4):c.1037-7T>A in the TYR gene has an allele frequency of 0.015 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.1037-7T>A 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 (PMID: 15381243; 18463683; 22294196; 25919014). 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 (PMID: 15381243). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4.

The TYR c.1037-7T>A variant is predicted to interfere with splicing. This variant has been reported in many individuals with oculocutaneous albinism (see for examples Hutton and Spritz 2008. PubMed ID: 18463683; Wang et al. 2015. PubMed ID: 25919014; Marti et al. 2017. PubMed ID: 28976636; Moon et al. 2022. PubMed ID: 35052368). A functional study using an exon trapping assay demonstrated that this variant causes abnormal splicing leading to premature protein termination (Goto et al. 2004. PubMed ID: 15381243, Fig. 5 reported as IVS2-10deltt-7t-a). Given all the evidence, we interpret c.1037-7T>A as pathogenic.