Submissions for variant NM_001193313.2(SUGCT):c.985C>T (p.Arg329Trp)

gnomAD frequency: 0.00490  dbSNP: rs137852860

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413225	SCV000490447	pathogenic	not provided	2022-05-16	criteria provided, single submitter	clinical testing	Reported as a variant possibly associated with an increased risk to develop autism spectrum disorder (Matsunami et al., 2014); Published functional studies demonstrate that the variant leads to the production of an insoluble and inactive protein (Marlaire et al., 2014); This variant is associated with the following publications: (PMID: 20818383, 23893049, 18926513, 31980526, 34426522, 24467814, 31028937, 28766179)
Fulgent Genetics, Fulgent Genetics	RCV000001923	SCV000893764	pathogenic	Glutaryl-CoA oxidase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000413225	SCV001037326	benign	not provided	2021-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001923	SCV003928585	pathogenic	Glutaryl-CoA oxidase deficiency	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: C7orf10 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276776 control chromosomes in the gnomAD database, including 10 homozygotes. c.895C>T has been reported in the literature in multiple individuals affected with Glutaryl-CoA Oxidase Deficiency and mitochondrial complex I disorder (Sherman_2008, Calvo_2010, Hou_2020), and some were reported as compound heterozygous with truncating variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014). The following publications have been ascertained in the context of this evaluation (PMID: 18926513, 20818383, 23893049, 31980526). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003421894	SCV004117197	pathogenic	SUGCT-related disorder	2023-06-06	criteria provided, single submitter	clinical testing	The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This gene is also known as C7orf10. This variant has been reported in the compound heterozygous or homozygous state in several individuals with glutaric aciduria type III (Sherman et al. 2008. PubMed ID: 18926513, described as c.895C>T based on transcript NM_024728). An in vitro study suggested that the p.Arg336Trp substitution impairs protein folding (Marlaire et al. 2014. PubMed ID: 23893049). It is currently thought that glutaric aciduria type III is potentially a benign biochemical phenomenon: pathogenic variants are reported in both healthy individuals and affected patients who present with inconsistent symptoms (Sherman et al. 2008. PubMed ID: 18926513; Marlaire et al. 2014. PubMed ID: 23893049). Although we classify the c.1006C>T variant as pathogenic based on its effect on the SUGCT protein, the contribution of this variant to clinical disease is uncertain.
OMIM	RCV000001923	SCV000022081	pathogenic	Glutaryl-CoA oxidase deficiency	2008-11-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000001923	SCV002074861	not provided	Glutaryl-CoA oxidase deficiency		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.