ClinVar Genomic variation as it relates to human health
NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)
Variation ID: 2523 Accession: VCV000002523.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q11.2 15: 22812252 (GRCh38) [ NCBI UCSC ] 15: 23060816 (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 Dec 10, 2017 May 12, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_144599.5:c.316G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_653200.2:p.Gly106Arg missense NM_001142275.1:c.91G>A NP_001135747.1:p.Gly31Arg missense NM_144599.4:c.[316G>A] NC_000015.10:g.22812252G>A NC_000015.9:g.23060816C>T NG_009056.1:g.31028G>A Q7RTP0:p.Gly106Arg - Protein change
- G106R, G31R
- Other names
- NIPA1, 316G-A, GLY106ARG
- Canonical SPDI
- NC_000015.10:22812251:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NIPA1 | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh37 |
271 | 674 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000002631.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2017 | RCV000516051.5 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2021 | RCV000713477.27 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003981.2 |
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
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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
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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
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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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Pathogenic
(Mar 07, 2017)
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criteria provided, single submitter
Method: research
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
inherited
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Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde
Accession: SCV000574453.1
First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017 |
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Pathogenic
(Jan 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000705178.2
First in ClinVar: Mar 08, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520049.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment:
PP1, PM2, PM6, PS1, PS3, PS4_moderate
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000541115.7
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the NIPA1 protein (p.Gly106Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the NIPA1 protein (p.Gly106Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (HSP) (PMID: 15643603, 15711826, 16267846, 21599812, 22302102, 24075313). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as G341A. ClinVar contains an entry for this variant (Variation ID: 2523). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NIPA1 function (PMID: 17166836, 19091982, 19620182, 20816793, 24128679). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248889.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448094.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present)
Sex: male
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Pathogenic
(Sep 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 6
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367366.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PM5,PP3,PP5.
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 6
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001451132.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 4
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000844089.2
First in ClinVar: Oct 20, 2018 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant results in the same amino acid change as another variant considered … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant results in the same amino acid change as another variant considered to be pathogenic (c.316G>C). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant impairs magnesium transport and results in protein accumulation in the endoplasmic reticulum (PMID 17166836, 19091982, 20816793). Computational tools predict that this variant is damaging. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 6
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072921.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.G106R in NIPA1 (NM_144599.5) has been reported previously in affected patients (Hedera P et al; Morais S et al). The variant has … (more)
The missense variant p.G106R in NIPA1 (NM_144599.5) has been reported previously in affected patients (Hedera P et al; Morais S et al). The variant has been previously reported as de novo mutation. The variant has been submitted to ClinVar as Pathogenic. The p.G106R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G106R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 106 of NIPA1 is conserved in all mammalian species. The nucleotide c.316 in NIPA1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Atrophy of the spinal cord (present) , Spinal muscular atrophy (present) , Abnormality of the dorsal column of the spinal cord (present) , Spastic paraplegia … (more)
Atrophy of the spinal cord (present) , Spinal muscular atrophy (present) , Abnormality of the dorsal column of the spinal cord (present) , Spastic paraplegia (present) (less)
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Pathogenic
(Jan 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105425.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Pathogenic
(Feb 01, 2005)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 6, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022788.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2018 |
Comment on evidence:
For discussion of the c.316G-A transition in the NIPA1 gene, resulting in a gly106-to-arg (R106R) substitution, that was found in compound heterozygous state in affected … (more)
For discussion of the c.316G-A transition in the NIPA1 gene, resulting in a gly106-to-arg (R106R) substitution, that was found in compound heterozygous state in affected members of 2 unrelated Chinese families with spastic paraplegia-6 (SPG6; 600363) by Chen et al. (2005), see 608145.0002. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Spastic paraplegia
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162007.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
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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
HelpTitle | Author | Journal | Year | Link |
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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Is NIPA1-associated hereditary spastic paraplegia always 'pure'? Further evidence of motor neurone disease and epilepsy as rare manifestations. | Tanti M | Neurogenetics | 2020 | PMID: 32500351 |
Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia. | Zhao M | Molecular diagnosis & therapy | 2019 | PMID: 31630374 |
Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing. | Kim A | Cerebellum (London, England) | 2019 | PMID: 31104286 |
Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. | Lu C | Journal of molecular medicine (Berlin, Germany) | 2018 | PMID: 29934652 |
Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. | Morais S | European journal of human genetics : EJHG | 2017 | PMID: 28832565 |
Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model. | Watanabe F | Journal of neuropathology and experimental neurology | 2013 | PMID: 24128679 |
TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation. | Martinez-Lage M | Acta neuropathologica | 2012 | PMID: 22302102 |
The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1. | Botzolakis EJ | Molecular and cellular neurosciences | 2011 | PMID: 20816793 |
The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. | Tsang HT | Human molecular genetics | 2009 | PMID: 19620182 |
Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism. | Zhao J | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2008 | PMID: 19091982 |
Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots. | Beetz C | Journal of the neurological sciences | 2008 | PMID: 18191948 |
NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. | Goytain A | The Journal of biological chemistry | 2007 | PMID: 17166836 |
Childhood-onset spastic paraplegia with NIPAL gene mutation. | Bien-Willner R | Journal of child neurology | 2006 | PMID: 17092466 |
Clinical and genetic study of a Brazilian family with spastic paraplegia (SPG6 locus). | Munhoz RP | Movement disorders : official journal of the Movement Disorder Society | 2006 | PMID: 16267846 |
A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. | Reed JA | Neurogenetics | 2005 | PMID: 15711826 |
Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. | Chen S | Human mutation | 2005 | PMID: 15643603 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NIPA1 | - | - | - | - |
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Text-mined citations for rs104894490 ...
HelpRecord last updated May 12, 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.