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

dbSNP: rs754002357

Total submissions: 6

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	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn392Metfs*9) in the GCDH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the GCDH protein. This variant is present in population databases (rs755038561, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with glutaric acidemia type I (PMID: 8900228, 10960496, 25762492). This variant is also known as 1209delG. ClinVar contains an entry for this variant (Variation ID: 370106). This variant disrupts a region of the GCDH protein in which other variant(s) (p.Met405Asnfs*14) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008118	SCV001167871	pathogenic	not provided	2021-12-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 47 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 8900228, 25762492, 25450519, 33064266, 34504725, 10960496)
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.
Baylor Genetics	RCV000410057	SCV004199270	pathogenic	Glutaric aciduria, type 1	2022-12-22	criteria provided, single submitter	clinical testing
National Institute of Mental Health and Neurosciences	RCV000410057	SCV000897926	likely pathogenic	Glutaric aciduria, type 1	2016-06-02	no assertion criteria provided	research