Submissions for variant NM_153006.3(NAGS):c.1268+2T>C

dbSNP: rs202041339

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761315	SCV000891300	likely pathogenic	Hyperammonemia, type III	2018-08-14	criteria provided, single submitter	clinical testing
Invitae	RCV000761315	SCV000932908	likely pathogenic	Hyperammonemia, type III	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the NAGS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NAGS are known to be pathogenic (PMID: 12594532). This variant is present in population databases (rs202041339, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NAGS-related conditions. ClinVar contains an entry for this variant (Variation ID: 623195). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000761315	SCV002018201	pathogenic	Hyperammonemia, type III	2020-11-25	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000761315	SCV002072849	likely pathogenic	Hyperammonemia, type III		criteria provided, single submitter	clinical testing	The splice donor variant c.1268+2T>C in NAGS (NM_153006.3) has been submitted to ClinVar as Likely Pathogenic. It has not been reported in literature in affected individuals. The c.1268+2T>C variant is observed in 1/15,172 (0.0066%) alleles from individuals of African background in gnomAD Exomes and in 1/1,322 (0.0756%) alleles from individuals of African background in 1000 Genomes. It affects an invariant splice nucleotide and ispredicted to disrupt splicing. For these reasons, this variant has been classified as Likely Pathogenic
Ambry Genetics	RCV002533865	SCV003530243	uncertain significance	Inborn genetic diseases	2021-09-01	criteria provided, single submitter	clinical testing	+2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000761315	SCV004199447	pathogenic	Hyperammonemia, type III	2023-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965571	SCV004778339	likely pathogenic	NAGS-related condition	2023-12-18	criteria provided, single submitter	clinical testing	The NAGS c.1268+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in individuals with NAGS-related disorders. This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in NAGS are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Natera, Inc.	RCV000761315	SCV001453370	likely pathogenic	Hyperammonemia, type III	2020-09-16	no assertion criteria provided	clinical testing