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

dbSNP: rs1553715351

Total submissions: 3

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 (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00147).