Submissions for variant NM_020988.3(GNAO1):c.724-8G>A

dbSNP: rs1085307876

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489428	SCV000577553	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26633542, 31130284)
New York Genome Center	RCV001291829	SCV001480454	likely pathogenic	Neurodevelopmental disorder with involuntary movements	2020-06-05	criteria provided, single submitter	clinical testing	The c.724-8G>A splice site variant in the GNAO1 gene has been reported in an individual with abnormality of the nervous system [PMID: 26633542]. This variant is not reported in gnomAD database indicating this is a rare allele. It is predicted to damage the natural splice acceptor site and create a stronger cryptic splice acceptor site in intron 6 [https://useast.ensembl.org/info/docs/tools/vep/index.html]. Based on the available evidence, the c.724-8G>A variant in the GNAO1 gene is classified as likely pathogenic.
Invitae	RCV001851316	SCV002240069	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 426965). This variant has been observed in individual(s) with GNAO1-related conditions (PMID: 31130284; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the GNAO1 gene. It does not directly change the encoded amino acid sequence of the GNAO1 protein.
Genetics and Molecular Pathology, SA Pathology	RCV002466519	SCV002761462	pathogenic	Developmental and epileptic encephalopathy, 17	2022-06-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001291829	SCV002766738	pathogenic	Neurodevelopmental disorder with involuntary movements	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function variants are found throughout the protein, and result in epileptic encephalopathy. Gain of function variants cluster near amino acid 184 and within the RGS binding domain, causing a neurodevelopmental disorder (PMID: 28747448, OMIM). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0212 - Non-canonical splice variant located in intron 6 of 8 and without proven consequence on splicing (no functional evidence available). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0508 - Abnormal splicing is predicted by in silico tools but the affected nucleotide is moderately conserved. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in several patients with generalised dystonia and psychomotor delay (ClinVar, PMID:26633542). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Ambry Genetics	RCV002526037	SCV003544358	pathogenic	Inborn genetic diseases	2022-07-06	criteria provided, single submitter	clinical testing	The c.724-8G>A intronic alteration results from a G to A substitution 8 nucleotides before coding exon 7 of the GNAO1 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with clinical features consistent with GNAO1 encephalopathies as a de novo occurrence or due to suspected parental germline mosaicism (Monies, 2019; Yang, 2021; Al Masseri, 2022; Liu, 2022; Wirth, 2022; Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV001291829	SCV003835761	pathogenic	Neurodevelopmental disorder with involuntary movements	2021-03-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003900029	SCV004713200	pathogenic	GNAO1-related disorder	2023-12-14	criteria provided, single submitter	clinical testing	The GNAO1 c.724-8G>A variant is predicted to interfere with splicing. This variant was reported in several individuals affected with GNAO1-related disorders; in several individuals, this was reported as de novo (see, for example, Retterer et al. 2016. PubMed ID: 26633542, supplemental data; Monies et al. 2019. PubMed ID: 31130284, Table S1; Yang et al. 2021. PubMed ID: 34122306; Al Masseri et al. 2022. PubMed ID: 35782616). In several studies, parental gonadal mosaicism for the variant was suspected (Al Masseri et al. 2022. PubMed ID: 35782616; Yang et al. 2021. PubMed ID: 34122306). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Pediatric Department, Peking University First Hospital	RCV001291829	SCV001499870	likely pathogenic	Neurodevelopmental disorder with involuntary movements	2021-02-03	no assertion criteria provided	clinical testing