Submissions for variant NM_018706.7(DHTKD1):c.1309G>T (p.Glu437Ter)

gnomAD frequency: 0.00010  dbSNP: rs138884194

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696727	SCV000825301	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu437*) in the DHTKD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818). This variant is present in population databases (rs138884194, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818). ClinVar contains an entry for this variant (Variation ID: 574714). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508294	SCV001714348	likely pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000696727	SCV002503749	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2020-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 437 in exon 7 (of 17) of DHTKD1 (p.Glu437*). It is expected to result in an absent or disrupted protein product. Loss of function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818 - PVS1). The variant is present in a large population cohort at a frequency of 0.006% (rs138884194, 18/282,894 alleles in gnomAD v2.1 - PM2). It has been reported compound heterozygous with a second pathogenic variant in a case diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818 - PM3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PM3.
CeGaT Center for Human Genetics Tuebingen	RCV001508294	SCV002544408	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	DHTKD1: PVS1:Moderate
MGZ Medical Genetics Center	RCV000696727	SCV002581384	likely pathogenic	2-aminoadipic 2-oxoadipic aciduria	2022-05-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002534332	SCV003700091	pathogenic	Inborn genetic diseases	2022-03-15	criteria provided, single submitter	clinical testing	The c.1309G>T (p.E437*) alteration, located in exon 7 (coding exon 7) of the DHTKD1 gene, consists of a G to T substitution at nucleotide position 1309. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 437. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration co-occurred with a second alteration in the DHTKD1 gene in an individual with alpha-aminoadipic and alpha-ketoadipic aciduria; however, information of the phase of these alterations was not provided (Hagen, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000696727	SCV003928491	likely pathogenic	2-aminoadipic 2-oxoadipic aciduria	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: DHTKD1 c.1309G>T (p.Glu437X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and associated with 2-Aminoadipic 2-Oxoadipic Aciduria in HGMD. The variant allele was found at a frequency of 6e-05 in 251488 control chromosomes. c.1309G>T has been reported in the literature in individuals affected with 2-Aminoadipic 2-Oxoadipic Aciduria (Hagen_2015) as well as in Charcot-Marie-Tooth Type 2Q (Dohrn_2017) and Amyotrophic Lateral Sclerosis (Osmanovic_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=3), likely pathogenic (n=2), uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.