ClinVar Miner

Submissions for variant NM_000523.4(HOXD13):c.209_210insGGCTGCGGCGGCGGCAGCGGC (p.Ala65_Ala71dup)

dbSNP: rs878854345
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Genomic Medicine, Nationwide Children's Hospital RCV001353047 SCV001547536 pathogenic Synpolydactyly type 1 2021-03-25 criteria provided, single submitter research The c.209_210insGGCTGCGGCGGCGGCAGCGGC variant is predicted to cause a 7-residue expansion of the polyalanine tract in exon 1 of HOXD13. This variant was first reported to cause dominant synpolydactyly more than 20 years ago and has been described in multiple unrelated synpolydactyly kindreds (PMID: 9207113). In our research study, we sequenced three members of a family with four documented generations of polysyndactyly. After identifying a similar variant (9-alanine dup) in a different family with this condition, we observed suggestive evidence of a similar event in this trio, and performed Sanger sequencing to confirm the 21-bp duplication in the proband and affected father. The variant is absent from population frequency databases (gnomAD). Functional studies of the polyalanine repeat in exon 1 have shown that an increase of the Ala repeat above a certain length (22 Ala) is associated with a shift in the localization of Hoxd13 from nuclear to cytoplasmic, where it forms large amorphous aggregates (PMID: 15333588). We interpret the variant as pathogenic.
Baylor Genetics RCV000016001 SCV004040672 pathogenic Syndactyly type 5 2023-04-13 criteria provided, single submitter clinical testing
OMIM RCV000016001 SCV000036268 pathogenic Syndactyly type 5 2005-11-01 no assertion criteria provided literature only

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