ClinVar Genomic variation as it relates to human health
NM_001005373.4(LRSAM1):c.2033G>A (p.Cys678Tyr)
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.
Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001005373.4(LRSAM1):c.2033G>A (p.Cys678Tyr)
Variation ID: 1803811 Accession: VCV001803811.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 127501130 (GRCh38) [ NCBI UCSC ] 9: 130263409 (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 17, 2022 Feb 20, 2024 Oct 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005373.4:c.2033G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005373.1:p.Cys678Tyr missense NM_001005374.4:c.2033G>A NP_001005374.1:p.Cys678Tyr missense NM_001190723.3:c.1952G>A NP_001177652.1:p.Cys651Tyr missense NM_001384142.1:c.2033G>A NP_001371071.1:p.Cys678Tyr missense NM_001384143.1:c.1934G>A NP_001371072.1:p.Cys645Tyr missense NM_001384144.1:c.1244G>A NP_001371073.1:p.Cys415Tyr missense NM_138361.5:c.2033G>A NP_612370.3:p.Cys678Tyr missense NR_168891.1:n.2562G>A non-coding transcript variant NR_168892.1:n.2386G>A non-coding transcript variant NC_000009.12:g.127501130G>A NC_000009.11:g.130263409G>A NG_032008.1:g.54645G>A NG_117561.1:g.661G>A LRG_373:g.54645G>A LRG_373t1:c.2033G>A LRG_373p1:p.Cys678Tyr - Protein change
- C415Y, C645Y, C651Y, C678Y
- Other names
- p.(Cys678Tyr)
- Canonical SPDI
- NC_000009.12:127501129: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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- 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 | ||
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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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LRSAM1 | - | - |
GRCh38 GRCh37 |
875 | 916 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 18, 2023 | RCV002468436.4 |
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
(Oct 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2P
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Gemeinschaftspraxis fuer Humangenetik Dresden
Accession: SCV002588744.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The variant p.(Cys678Tyr) is not listed in HGMD 2022.3, ClinVar, gnomAD or in the NCBI dbSNP. In LOVD the variant is listed as likely pathogenic. … (more)
The variant p.(Cys678Tyr) is not listed in HGMD 2022.3, ClinVar, gnomAD or in the NCBI dbSNP. In LOVD the variant is listed as likely pathogenic. In HGMD on same aminoacid position is p.(Cys678Gly) listed as pathogenic for axonal neuropathy. Multiple lines of computational evidence support a deleterious effect (SIFT, MutationTaster2021, PolyPhen-2, AGVGD). The variant resides in the RING domain (amino acids 675-710) of the E3 ubiquitin protein ligase LRSAM. These domain contains highly conserved cysteines and histidine separated by a variable number of other amino acid residues. This cysteine-histidine lattice binds two central zinc ions that are essential for the working out of the three-dimensional structure of the RING domain. This is essential for the binding of the ubiquitin-conjugating enzymes. A mutation in the RING domain may lead to its destabilization and impaired E3 ubiquitin ligase activity (Palaima et al., 2021). In summary, the p.(Cys678Tyr) variant meets our criteria to be classified as likely pathogenic. ACMG: PM1, PM2, PM5, PP3 (ACMG Guidelines, 2015). (less)
Sex: male
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Uncertain significance
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2P
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003201696.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 678 of the LRSAM1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 678 of the LRSAM1 protein (p.Cys678Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1803811). 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 LRSAM1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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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LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond. | Palaima P | Orphanet journal of rare diseases | 2021 | PMID: 33568173 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 29, 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.