NM_052876.4(NACC1):c.892C>T (p.Arg298Trp) AND Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000477683.16

Allele description [Variation Report for NM_052876.4(NACC1):c.892C>T (p.Arg298Trp)]

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

Gene:

NACC1:nucleus accumbens associated 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

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

HGVS:

NC_000019.10:g.13136099C>T
NM_052876.4:c.892C>TMANE SELECT
NP_443108.1:p.Arg298Trp
NC_000019.9:g.13246913C>T
NM_052876.2:c.892C>T
NM_052876.3:c.892C>T
p.R298W

Protein change:

R298W; ARG298TRP

Links:

OMIM: 610672.0001; dbSNP: rs1060505041

NCBI 1000 Genomes Browser:

rs1060505041

Molecular consequence:

NM_052876.4:c.892C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM)
Identifiers:: MONDO: MONDO:0044306; MedGen: C4479333; OMIM: 617393

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000564235	OMIM	no assertion criteria provided	Pathogenic (Mar 28, 2017)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000622158	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (Schoch K et al. (Am J Hum Genet 2017))	Pathogenic (Feb 2, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000992791	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002011957	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10767337, 11241840, 25741868
SCV002018190	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002506742	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Likely pathogenic (May 21, 2021)	germline	clinical testing	Citation Link,
SCV005091455	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation	PubMed (1) [See all records that cite this PMID]
SCV005368705	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	no assertion criteria provided	Pathogenic (May 11, 2023)	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation
White	de novo	yes	1	not provided	not provided	not provided	no	clinical testing

Citations

PubMed

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

Schoch K, Meng L, Szelinger S, Bearden DR, Stray-Pedersen A, Busk OL, Stong N, Liston E, Cohn RD, Scaglia F, Rosenfeld JA, Tarpinian J, Skraban CM, Deardorff MA, Friedman JN, Akdemir ZC, Walley N, Mikati MA, Kranz PG, Jasien J, McConkie-Rosell A, McDonald M, et al.

Am J Hum Genet. 2017 Feb 2;100(2):343-351. doi: 10.1016/j.ajhg.2016.12.013. Epub 2017 Jan 26.

PubMed [citation]

PMID:: 28132692
PMCID:: PMC5294886

Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.

Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D, Sampson JR, Clarke A.

Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Erratum in: Hum Mol Genet 2000 Jul 1;9(11):1717.

PubMed [citation]

PMID:: 10767337

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000564235.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 7 unrelated patients with neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM; 617393), Schoch et al. (2017) identified a recurrent de novo heterozygous c.892C-T transition (c.892C-T, NM_052876.3) in the NACC1 gene, resulting in an arg298-to-trp (R298W) substitution at a highly conserved residue. One of the patients (patient 7) was mosaic for the mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. However, Schoch et al. (2017) noted that a different substitution at the same codon (R298L) had been observed in 1 individual in the ExAC database and in 4 individuals in the Gnome Aggregation Database (gnomAD). Functional studies of the variant and studies of patient cells were not performed. The mutation occurred at a CpG dinucleotide. The finding of the same mutation in 7 unrelated patients with a similar phenotype was statistically significant (Bonferroni corrected p = 1.25 x 10(-14)).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH, SCV000622158.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	no	clinical testing	PubMed (1)

Description

Pathogenic variant based on genotype/phenotype relationship. This patient has been reported in PMID 28132692.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV000992791.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002011957.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018190.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002506742.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Solve-RD Consortium, SCV005091455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	PubMed (1)

Description

Variant confirmed as disease-causing by referring clinical team

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV005368705.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	Blood	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2025

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