VCV000190977.11 - ClinVar

NM_022787.4(NMNAT1):c.53A>G (p.Asn18Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_022787.3(NMNAT1):c.[53A>G];[769G>A]

Identifiers

NM_022787.4(NMNAT1):c.53A>G (p.Asn18Ser)

Variation ID: 190977 Accession: VCV000190977.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 9972126 (GRCh38) [ NCBI UCSC ] 1: 10032184 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 2, 2015	Apr 6, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022787.4:c.53A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_073624.2:p.Asn18Ser	missense
NM_001297778.1:c.53A>G	NP_001284707.1:p.Asn18Ser	missense
NM_001297779.2:c.53A>G	NP_001284708.1:p.Asn18Ser	missense
NC_000001.11:g.9972126A>G
NC_000001.10:g.10032184A>G
NG_032954.1:g.33699A>G

... more HGVS ... less HGVS

Protein change

N18S

Other names

Canonical SPDI

NC_000001.11:9972125:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA235735 OMIM: 608700.0014 dbSNP: rs748902766 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NMNAT1		-	-	GRCh38 GRCh37	198	246

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV000171148.5
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2019	RCV001075815.4
Leber congenital amaurosis 9	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV001256641.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 19, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241451.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Mar 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 9 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002246393.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 24940029‚ 29184169‚ 30004997 Comment: 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 … (more) 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 create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190977). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 24940029, 29184169, 30004997; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs748902766, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 18 of the NMNAT1 protein (p.Asn18Ser). (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis 9 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805075.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 9 Affected status: yes Allele origin: germline	3billion Accession: SCV002058433.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:30004997 PMID:30004997 PMID:29184169 PMID:29184169 PMID:24940029 PMID:24940029 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000190977, PMID:24940029, PS1_S). The … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000190977, PMID:24940029, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24940029, 30004997, 29184169, PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.928, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Leber congenital amaurosis 9 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Visual impairment (present) , Abnormal retinal morphology (present)
Pathogenic (Apr 09, 2021)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001569086.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (2) PubMed: 29184169‚ 30004997 Comment on evidence: For discussion of the c.53A-G transition in the NMNAT1 gene, resulting in an asn18-to-ser (N18S) substitution, that was found in compound heterozygous state in patients … (more) For discussion of the c.53A-G transition in the NMNAT1 gene, resulting in an asn18-to-ser (N18S) substitution, that was found in compound heterozygous state in patients with early-onset retinal dystrophy and severe macular atrophy (LCA9; 608553) by Nash et al. (2018) and Kumaran et al. (2021), see 608700.0002. (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 9 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001433012.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Number of individuals with the variant: 4
Likely pathogenic (-)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000221344 appears to (...more) Source: NCBI	Not provided Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000221344.1 First in ClinVar: Jun 02, 2015 Last updated: Jun 02, 2015	Indication for testing: Vision phenotype
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

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 create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190977). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 24940029, 29184169, 30004997; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs748902766, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 18 of the NMNAT1 protein (p.Asn18Ser).

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000190977, PMID:24940029, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24940029, 30004997, 29184169, PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.928, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Leber congenital amaurosis 9 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A NOVEL CASE SERIES OF NMNAT1-ASSOCIATED EARLY-ONSET RETINAL DYSTROPHY: EXTENDING THE PHENOTYPIC SPECTRUM.	Kumaran N	Retinal cases & brief reports	2021	PMID: 30004997
NMNAT1 variants cause cone and cone-rod dystrophy.	Nash BM	European journal of human genetics : EJHG	2018	PMID: 29184169
Novel compound heterozygous NMNAT1 variants associated with Leber congenital amaurosis.	Siemiatkowska AM	Molecular vision	2014	PMID: 24940029

Text-mined citations for rs748902766 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_022787.4(NMNAT1):c.53A>G (p.Asn18Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs748902766 ...