ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.1173del (p.Asn392fs) (rs754002357)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410057 SCV000485337 likely pathogenic Glutaric aciduria, type 1 2015-11-19 criteria provided, single submitter clinical testing
Invitae RCV000410057 SCV000831180 pathogenic Glutaric aciduria, type 1 2018-02-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GCDH gene (p.Asn392Metfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the GCDH protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous or in combination with another GCDH variant in individuals affected with glutaric acidemia type I (PMID: 8900228, 10960496, 25762492). ClinVar contains an entry for this variant (Variation ID: 370106). This variant is also known as 1209delG in the literature. For these reasons, this variant has been classified as Pathogenic. Studies have shown that fibroblasts isolated from affected individuals why carry this variant have low residual GCDH enzyme activity (PMID: 10960496).
GeneDx RCV001008118 SCV001167871 likely pathogenic not provided 2018-09-28 criteria provided, single submitter clinical testing The c.1173delG variant has been published in patients with glutaric aciduria type 1 both in the homozygous state and with a second GCDH variant (Anikster et al. 1996; Gupta et al. 2015). The c.1173delG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.1173delG variant causes a frameshift starting with codon Asparagine 392, changes this amino acid to a Methionine residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asn392MetfsX9. This variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret this variant as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410057 SCV001482118 pathogenic Glutaric aciduria, type 1 2021-02-01 criteria provided, single submitter clinical testing Variant summary: GCDH c.1173delG (p.Asn392MetfsX9) 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 by our laboratory. The variant allele was found at a frequency of 8e-06 in 251350 control chromosomes. c.1173delG has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (e.g. Anikster_1996, Busquets_2000, Gupta_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Busquets_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
National Institute of Mental Health and Neurosciences RCV000410057 SCV000897926 likely pathogenic Glutaric aciduria, type 1 2016-06-02 no assertion criteria provided research

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