VCV001050789.2 - ClinVar

NM_022787.4(NMNAT1):c.299+526_*968dup

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.

(2)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022787.4(NMNAT1):c.299+526_*968dup

Variation ID: 1050789 Accession: VCV001050789.2

Type and length

Duplication, 7,369 bp

Location

Cytogenetic: 1p36.22 1: 9976248-9976249 (GRCh38) [ NCBI UCSC ] 1: 10036306-10036307 (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	Apr 13, 2021	Apr 13, 2021	Apr 9, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_022787.4:c.299+256_*968dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor splice donor
NM_022787.4:c.299+526_*968dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor splice donor
NM_001297778.1:c.299+526_*968dup		splice acceptor splice donor
NC_000001.11:g.9976301_9983669dup
NC_000001.10:g.10036359_10043727dup
NG_032954.1:g.37874_45242dup

... more HGVS ... less HGVS

Protein change

Other names

7.4-KB DUP

Canonical SPDI

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.

Links

OMIM: 608700.0010 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.
Leber congenital amaurosis 9	Pathogenic (1)	no assertion criteria provided	Apr 9, 2021	RCV001358653.2
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis	Pathogenic (1)	no assertion criteria provided	Apr 9, 2021	RCV001358652.2

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 (Apr 09, 2021)	no assertion criteria provided Method: literature only	SPONDYLOEPIPHYSEAL DYSPLASIA, SENSORINEURAL HEARING LOSS, IMPAIRED INTELLECTUAL DEVELOPMENT, AND LEBER CONGENITAL AMAUROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV001554449.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (1) PubMed: 32533184 Abad-Morales, V., Wert, A., Ruiz (more...) Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform. Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article. Comment on evidence: Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy … (more) Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy (P3; 947-13) with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication (c.299+526_Ter968dup, NM_022787.3) involving exons 4 and 5 of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The unaffected parents were heterozygous for the duplication, which was found to be embedded in a common haplotype, indicating that it represented a founder mutation. The authors suggested that the Alu elements flanking the duplicated fragment, AluSx and AluSx3, might have mediated a tandem duplication event by nonallelic homologous recombination. Analysis of patient fibroblasts showed a 4-fold downregulation of NMNAT1, and RT-PCR revealed a heterogeneous population of aberrant mRNA isoforms, variably showing partial retention of intron 3, duplication of exon 4, and duplication of exon 4 and part of exon 5, as well as some wildtype transcript. In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation (c.439+5G-T) in intron 4 of the NMNAT1 gene. Her unaffected father, who was of Bulgarian origin, was heterozygous for the splicing mutation; DNA was unavailable from her biological mother, as the child was born from an ovum donation procedure. Total NMNAT1 expression in the proband was reduced by approximately 25% compared to controls. Expression assays indicated that the duplication decreases the levels of the known NMNAT1 canonical isoform 1 and alternative isoform 2, whereas the splicing mutation alters the relative expression of NMNAT1 isoforms. Leber Congenital Amaurosis 9 Bedoni et al. (2020) performed PCR screening in a Spanish cohort of 76 patients with Leber congenital amaurosis (LCA) or early-onset retinal dystrophy and identified a 6-year-old boy with LCA (LCA9; 608553) who was compound heterozygous for the common E257K variant in the NMNAT1 gene (608700.0002) and the 7.4-bp duplication. Haplotype analysis in the Spanish boy revealed rare heterozygous SNP genotypes in proximity to the duplication which were shared with the Italian patients, indicating a common and likely remote ancestral genetic event. (less)
Pathogenic (Apr 09, 2021)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001554450.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (1) PubMed: 32533184 Abad-Morales, V., Wert, A., Ruiz (more...) Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform. Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article. Comment on evidence: Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy … (more) Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy (P3; 947-13) with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication (c.299+526_Ter968dup, NM_022787.3) involving exons 4 and 5 of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The unaffected parents were heterozygous for the duplication, which was found to be embedded in a common haplotype, indicating that it represented a founder mutation. The authors suggested that the Alu elements flanking the duplicated fragment, AluSx and AluSx3, might have mediated a tandem duplication event by nonallelic homologous recombination. Analysis of patient fibroblasts showed a 4-fold downregulation of NMNAT1, and RT-PCR revealed a heterogeneous population of aberrant mRNA isoforms, variably showing partial retention of intron 3, duplication of exon 4, and duplication of exon 4 and part of exon 5, as well as some wildtype transcript. In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation (c.439+5G-T) in intron 4 of the NMNAT1 gene. Her unaffected father, who was of Bulgarian origin, was heterozygous for the splicing mutation; DNA was unavailable from her biological mother, as the child was born from an ovum donation procedure. Total NMNAT1 expression in the proband was reduced by approximately 25% compared to controls. Expression assays indicated that the duplication decreases the levels of the known NMNAT1 canonical isoform 1 and alternative isoform 2, whereas the splicing mutation alters the relative expression of NMNAT1 isoforms. Leber Congenital Amaurosis 9 Bedoni et al. (2020) performed PCR screening in a Spanish cohort of 76 patients with Leber congenital amaurosis (LCA) or early-onset retinal dystrophy and identified a 6-year-old boy with LCA (LCA9; 608553) who was compound heterozygous for the common E257K variant in the NMNAT1 gene (608700.0002) and the 7.4-bp duplication. Haplotype analysis in the Spanish boy revealed rare heterozygous SNP genotypes in proximity to the duplication which were shared with the Italian patients, indicating a common and likely remote ancestral genetic event. (less)

Citation text

Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform. Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.

Citation text

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.	Abad-Morales V	International journal of molecular sciences	2021	PMID: 33668384
An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.	Bedoni N	Human molecular genetics	2020	PMID: 32533184

Text-mined citations for this variant ...

Record last updated Mar 18, 2023

ClinVar Genomic variation as it relates to human health

NM_022787.4(NMNAT1):c.299+526_*968dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...