ClinVar Miner

Submissions for variant NM_000187.4(HGD):c.1290_1300del (p.Lys431fs)

dbSNP: rs1553715351
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522957 SCV000617864 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing The c.1290_1300del11 variant in the HGD gene has been reported previously using alternate nomenclature (c.1282_1292delGAGCCACTCAA) in association with autosomal recessive alkaptonuria, however, additional clinical information was not provided (Zatkova et al., 2012). The c.1290_1300del11 variant causes a frameshift starting with codon Lysine 431, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Lys431HisfsX11. This variant is predicted to cause loss of normal protein function through protein truncation as the last fifteen amino acids are lost and replaced with ten incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein. The c.1290_1300del11 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1290_1300del11 as a variant of uncertain significance.
Invitae RCV000793930 SCV000933310 likely pathogenic Alkaptonuria 2022-06-27 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449571). This premature translational stop signal has been observed in individual(s) with alkaptonuria (PMID: 23430897, 25681086; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys431Hisfs*11) in the HGD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the HGD protein.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences RCV000793930 SCV004098702 pathogenic Alkaptonuria no assertion criteria provided research The variant was originally described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (, DB-ID: AKU_00147).

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