ClinVar Miner

Submissions for variant NM_003924.4(PHOX2B):c.778_779insGGCGGCGGCGGCAGCGGCAGCGGCGGCAGC (p.Ala260delinsGlyArgArgArgGlnArgGlnArgArgGlnPro)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224715 SCV003920314 pathogenic Neuroblastoma, susceptibility to, 2; Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease 2021-03-30 criteria provided, single submitter clinical testing PHOX2B NM_003924.3 exon 3 p.Ala251_Ala260dup (c.750_779dup): This variant has been reported in the literature in several individuals with Congenital Central Hypoventilation Syndrome (CCHS) (Weese-Mayer 2003 PMID:14608649, Weese-Mayer 2010 PMID:20208042). This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 10 Alanine amino acids at position 251 and is not predicted to alter the reading frame. Wild type repeats of this region (known as the Polyalanine Repeat Expansion (PARMs)) are typically identified as 20 repeats; expansions to 24-33 repeats are known to be pathogenic (Weese-Mayer 2010 PMID:20208042), though repeat sizes of 24 and 25 have reduced penetrance. This variant represents an increase of 10 Alanine repeats for a total of 30 repeats and is within the disease associated range. Therefore, this variant is classified as pathogenic.

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