ClinVar Miner

Submissions for variant NM_005029.4(PITX3):c.640_656del (p.Ala214fs) (rs1411557416)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545169 SCV000644789 uncertain significance Anterior segment dysgenesis 1; Cataract 11 2018-06-01 criteria provided, single submitter clinical testing This sequence change deletes 17 nucleotides from exon 4 of the PITX3 mRNA (c.640_656del), causing a frameshift at codon 214. This creates a premature translational stop signal in the last exon of the PITX3 mRNA (p.Ala214Argfs*42). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acids of the PITX3 protein. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in a family affected with autosomal recessive anterior segment dysgenesis and microphthalmia, but without cataract or a neurological phenotype. Heterozygosity for the same variant was confirmed in each of the unaffected parents (PMID: 21836522). Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 89 amino acids of the PITX3 protein are critical for its function. In summary, this is a rare truncating variant that has been observed in an affected family. However, without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance.

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