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

dbSNP: rs1060505041

Total submissions: 11

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
Invitae	RCV000522576	SCV001580866	pathogenic	not provided	2021-05-19	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been reported to be de novo in seven individuals characterized by infantile epilepsy, cataracts, profound developmental delay, and a variety of other findings (PMID: 28132692). ClinVar contains an entry for this variant (Variation ID: 417784). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 298 of the NACC1 protein (p.Arg298Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 28132692, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). 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.