Submissions for variant NM_052876.4(NACC1):c.892C>T (p.Arg298Trp)

dbSNP: rs1060505041

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522576	SCV000617944	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31231135, 31628766, 30842647, 31036916, 31216405, 28132692, 34869110)
Undiagnosed Diseases Network, NIH	RCV000477683	SCV000622158	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2017-02-02	criteria provided, single submitter	clinical testing	Pathogenic variant based on genotype/phenotype relationship. This patient has been reported in PMID 28132692.
Ambry Genetics	RCV000624692	SCV000740687	likely pathogenic	Inborn genetic diseases	2017-06-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000477683	SCV000992791	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2022-12-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000522576	SCV001447350	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522576	SCV001580866	pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 298 of the NACC1 protein (p.Arg298Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile epilepsy, cataracts, and profound developmental delay (PMID: 28132692). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 417784). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NACC1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000477683	SCV002011957	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2024-01-18	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11241840). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815 /PMID: 10767337 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000477683	SCV002018190	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2023-06-29	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000477683	SCV002506742	likely pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2021-05-21	criteria provided, single submitter	clinical testing	The c.892C>T (p.Arg298Trp) variant identified in the NACC1 gene substitutes a well conserved Arginine for Tryptophan at amino acid 298/528 (exon2/6). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.027) and Benign (REVEL; score:0.3639) to the function of the canonical transcript. This variant is reported as Likely Pathogenic / Pathogenic in ClinVar (VarID:417784) and has been identified in many affected individuals in the literature [PMID:28132692; PMID:30842647]. Given its presence in many affected individuals in the literature and its absence in population databases, the c.892C>T (p.Arg298Trp) variant identified in the NACC1 gene is reported as Likely Pathogenic.
OMIM	RCV000477683	SCV000564235	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2017-03-28	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV001824794	SCV002074832	not provided	NACC1-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-07-2020 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.
Solve-RD Consortium	RCV000477683	SCV005091455	likely pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team
Undiagnosed Diseases Network, NIH	RCV000477683	SCV005368705	pathogenic	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	2023-05-11	no assertion criteria provided	clinical testing