PM3, BS3, PP3
ClinVar Genomic variation as it relates to human health
NM_022787.4(NMNAT1):c.37G>A (p.Ala13Thr)
Germline
Classification
Help
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.
(9)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(4); Uncertain significance(2)
Pathogenic(1); Likely pathogenic(4); Uncertain significance(2)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_022787.4(NMNAT1):c.37G>A (p.Ala13Thr)
Variation ID: 195375 Accession: VCV000195375.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 9972110 (GRCh38) [ NCBI UCSC ] 1: 10032168 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 29, 2015 Oct 13, 2024 Oct 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022787.4:c.37G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_073624.2:p.Ala13Thr missense NM_001297778.1:c.37G>A NP_001284707.1:p.Ala13Thr missense NM_001297779.2:c.37G>A NP_001284708.1:p.Ala13Thr missense NC_000001.11:g.9972110G>A NC_000001.10:g.10032168G>A NG_032954.1:g.33683G>A Q9HAN9:p.Ala13Thr - Protein change
- A13T
- Other names
- -
- Canonical SPDI
- NC_000001.11:9972109:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
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0.00120 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00016
Exome Aggregation Consortium (ExAC) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00056
The Genome Aggregation Database (gnomAD) 0.00057
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00100
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00125
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 3, 2024 | RCV000175940.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2019 | RCV001074101.2 | |
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2023 | RCV001256640.8 | |
|
NMNAT1-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Sep 3, 2024 | RCV004757972.1 |
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. |
|
|---|---|---|---|---|---|
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Uncertain significance
(Jan 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227515.5
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 3
Sex: mixed
|
|
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Uncertain significance
(Mar 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499106.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PM3, BS3, PP3
|
|
|
Likely pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 9
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517339.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
|
|
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Pathogenic
(Jan 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239670.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Likely pathogenic
(May 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 9
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512630.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting
Geographic origin: Brazil
|
|
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Likely pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 9
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001699418.4
First in ClinVar: Jun 08, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the NMNAT1 protein (p.Ala13Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the NMNAT1 protein (p.Ala13Thr). This variant is present in population databases (rs138613460, gnomAD 0.2%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 22842227, 22842229, 32865313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195375). 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 expected to disrupt NMNAT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NMNAT1 function (PMID: 26018082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
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Likely pathogenic
(Oct 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002008744.4
First in ClinVar: Nov 06, 2021 Last updated: Oct 13, 2024 |
Comment:
In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in … (more)
In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 26018082); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22842229, 22842227, 32641690, 32865313, 34041853, 22842230, 38219857, 26018082) (less)
|
|
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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: SCV001433011.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Number of individuals with the variant: 4
|
|
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Uncertain significance
(Sep 03, 2024)
|
no assertion criteria provided
Method: clinical testing
|
NMNAT1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005361754.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The NMNAT1 c.37G>A variant is predicted to result in the amino acid substitution p.Ala13Thr. This variant has been reported with another likely causative variant (three … (more)
The NMNAT1 c.37G>A variant is predicted to result in the amino acid substitution p.Ala13Thr. This variant has been reported with another likely causative variant (three individuals who also carried the p.Val98Gly variant) or a variant of uncertain significance (one case) in patients with Leber congenital amaurosis (Supplementary Table 3 in Perrault et al. 2012. PubMed ID: 22842229, Table 1, P18; Falk et al. 2012. PubMed ID: 22842227, Table 1, LCA-3; Porto et al. 2017. PubMed ID: 29186038, Table 2, patient FBP_57; Koenekoop et al. 2012. PubMed ID: 22842230, Patient MOGL3698). Functional, expression, and localization studies suggested that this variant is similar to wild-type (Sasaki et al. 2015. PubMed ID: 26018082). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the NMNAT1 protein (p.Ala13Thr). This variant is present in population databases (rs138613460, gnomAD 0.2%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 22842227, 22842229, 32865313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195375). 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 expected to disrupt NMNAT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NMNAT1 function (PMID: 26018082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 26018082); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22842229, 22842227, 32641690, 32865313, 34041853, 22842230, 38219857, 26018082)
Comment:
The NMNAT1 c.37G>A variant is predicted to result in the amino acid substitution p.Ala13Thr. This variant has been reported with another likely causative variant (three individuals who also carried the p.Val98Gly variant) or a variant of uncertain significance (one case) in patients with Leber congenital amaurosis (Supplementary Table 3 in Perrault et al. 2012. PubMed ID: 22842229, Table 1, P18; Falk et al. 2012. PubMed ID: 22842227, Table 1, LCA-3; Porto et al. 2017. PubMed ID: 29186038, Table 2, patient FBP_57; Koenekoop et al. 2012. PubMed ID: 22842230, Patient MOGL3698). Functional, expression, and localization studies suggested that this variant is similar to wild-type (Sasaki et al. 2015. PubMed ID: 26018082). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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:
PM3, BS3, PP3
Comment:
ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the NMNAT1 protein (p.Ala13Thr). This variant is present in population databases (rs138613460, gnomAD 0.2%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 22842227, 22842229, 32865313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195375). 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 expected to disrupt NMNAT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NMNAT1 function (PMID: 26018082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 26018082); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22842229, 22842227, 32641690, 32865313, 34041853, 22842230, 38219857, 26018082)
Comment:
The NMNAT1 c.37G>A variant is predicted to result in the amino acid substitution p.Ala13Thr. This variant has been reported with another likely causative variant (three individuals who also carried the p.Val98Gly variant) or a variant of uncertain significance (one case) in patients with Leber congenital amaurosis (Supplementary Table 3 in Perrault et al. 2012. PubMed ID: 22842229, Table 1, P18; Falk et al. 2012. PubMed ID: 22842227, Table 1, LCA-3; Porto et al. 2017. PubMed ID: 29186038, Table 2, patient FBP_57; Koenekoop et al. 2012. PubMed ID: 22842230, Patient MOGL3698). Functional, expression, and localization studies suggested that this variant is similar to wild-type (Sasaki et al. 2015. PubMed ID: 26018082). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients. | Sallum JMF | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 32865313 |
| Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. | Sasaki Y | The Journal of biological chemistry | 2015 | PMID: 26018082 |
| Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. | Koenekoop RK | Nature genetics | 2012 | PMID: 22842230 |
| Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. | Perrault I | Nature genetics | 2012 | PMID: 22842229 |
| NMNAT1 mutations cause Leber congenital amaurosis. | Falk MJ | Nature genetics | 2012 | PMID: 22842227 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NMNAT1 | - | - | - | - |
Text-mined citations for rs138613460 ...
HelpThese 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 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.