ClinVar Genomic variation as it relates to human health
NM_000434.4(NEU1):c.893C>T (p.Ala298Val)
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_000434.4(NEU1):c.893C>T (p.Ala298Val)
Variation ID: 2457 Accession: VCV000002457.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.33 6: 31860170 (GRCh38) [ NCBI UCSC ] 6: 31827947 (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 6, 2016 Feb 14, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000434.4:c.893C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000425.1:p.Ala298Val missense NC_000006.12:g.31860170G>A NC_000006.11:g.31827947G>A NG_008201.1:g.7763C>T Q99519:p.Ala298Val - Protein change
- A298V
- Other names
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- Canonical SPDI
- NC_000006.12:31860169: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.
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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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NEU1 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
285 | 295 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Aug 29, 2016 | RCV000002561.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2023 | RCV001314931.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV003323347.2 |
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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Likely pathogenic
(Aug 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Sialidosis type 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000461928.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The NEU1 c.893C>T (p.Ala298Val) missense variant has been reported in two individuals with mucolipidosis, type 1, including one who carried the variant in a homozygous … (more)
The NEU1 c.893C>T (p.Ala298Val) missense variant has been reported in two individuals with mucolipidosis, type 1, including one who carried the variant in a homozygous state and one who carried the variant in a compound heterozygous state (Lukong et al. 2000; Pattison et al. 2004). The p.Ala298Val was absent from 20 controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using COS-7 cells and sialidosis-deficient human fibroblasts demonstrated that the p.Ala298Val variant has very low sialidase activity compared to wild type NEU1, and the p.Ala298Val variant also results in aberrant localization of the NEU1 protein, likely due to protein misfolding (Lukong et al. 2000; Pattison et al. 2004). Based on the evidence, the p.Ala298Val variant is classified as likely pathogenic for mucolipidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sialidosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004028701.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: NEU1 c.893C>T (p.Ala298Val) results in a non-conservative amino acid change located in the Sialidase domain (IPR011040) of the encoded protein sequence. Four of … (more)
Variant summary: NEU1 c.893C>T (p.Ala298Val) results in a non-conservative amino acid change located in the Sialidase domain (IPR011040) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246526 control chromosomes (gnomAD v2.1 Exomes dataset). This frequency is not significantly higher than estimated for a pathogenic variant in NEU1 causing Sialidosis (4.1e-05 vs 0.0011), allowing no conclusion about variant significance. c.893C>T has been reported in the literature in at least one homozygote and one compound heterozygote affected with Sialidosis (e.g., Lukong_2000, Pattison_2004). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% enzymatic activity, which is likely due to protein misfolding (e.g, Lukong_2000, Lukong_2001, Pattison_2004). The following publications have been ascertained in the context of this evaluation (PMID: 10767332, 11279074, 14695530). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Dec 09, 2023)
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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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Invitae
Accession: SCV001505483.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 298 of the NEU1 protein (p.Ala298Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 298 of the NEU1 protein (p.Ala298Val). This variant is present in population databases (rs104893981, gnomAD 0.07%). This missense change has been observed in individual(s) with sialidosis (PMID: 10767332, 14695530). ClinVar contains an entry for this variant (Variation ID: 2457). 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 not expected to disrupt NEU1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NEU1 function (PMID: 10767332, 11279074, 14695530). 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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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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SIALIDOSIS, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022719.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 20, 2018 |
Comment on evidence:
For discussion of the ala298-to-val (A298V) mutation in the NEU1 gene that was found in compound heterozygous state in a patient with type II sialidosis … (more)
For discussion of the ala298-to-val (A298V) mutation in the NEU1 gene that was found in compound heterozygous state in a patient with type II sialidosis (256550) by Pattison et al. (2004), see 608272.0014. (less)
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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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Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression. | Pattison S | Human mutation | 2004 | PMID: 14695530 |
Mutations in sialidosis impair sialidase binding to the lysosomal multienzyme complex. | Lukong KE | The Journal of biological chemistry | 2001 | PMID: 11279074 |
Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex. | Lukong KE | Human molecular genetics | 2000 | PMID: 10767332 |
Text-mined citations for rs104893981 ...
HelpRecord last updated Feb 20, 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.