Variant summary: RMRP n.41G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 7.7e-06 in 130626 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. n.41G>A (also known as g.40G>A) has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (Bonafe_2005, Bordon_2010). These data indicate that the variant may be associated with disease. At least one functional study reports this variant altered the structure of the P3 apical stem loop, which, in contrast to the wild type P3 domain is not efficiently bound by the Rpp20-Rpp25 heterodimer (Welting_2008). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NR_003051.4(RMRP):n.42G>A
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.
(4)
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.
Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NR_003051.4(RMRP):n.42G>A
Variation ID: 550994 Accession: VCV000550994.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 35657978 (GRCh38) [ NCBI UCSC ] 9: 35657975 (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 Aug 5, 2018 Feb 14, 2024 Sep 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNR_003051.4:n.42G>A NC_000009.12:g.35657978C>T NC_000009.11:g.35657975C>T NG_017041.1:g.5041G>A NG_033120.1:g.4689C>T NG_116211.1:g.514C>T LRG_163:g.5041G>A LRG_163t1:n.41G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000009.12:35657977:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| RMRP | - | - |
GRCh38 GRCh37 |
785 | 865 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000665942.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 21, 2023 | RCV001378693.8 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Metaphyseal chondrodysplasia, McKusick type
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790154.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
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Likely pathogenic
(Oct 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Metaphyseal chondrodysplasia, McKusick type
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015180.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: RMRP n.41G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 7.7e-06 in 130626 control chromosomes … (more)
Variant summary: RMRP n.41G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 7.7e-06 in 130626 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. n.41G>A (also known as g.40G>A) has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (Bonafe_2005, Bordon_2010). These data indicate that the variant may be associated with disease. At least one functional study reports this variant altered the structure of the P3 apical stem loop, which, in contrast to the wild type P3 domain is not efficiently bound by the Rpp20-Rpp25 heterodimer (Welting_2008). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Metaphyseal chondrodysplasia, McKusick type
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572840.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Non-coding variant. The variant has been reported … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Non-coding variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000550994). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Erythroid hyperplasia (present) , Coombs-positive hemolytic anemia (present) , Short stature (present) , Reticulocytosis (present) , Hepatosplenomegaly (present) , Leukopenia (present) , Cataract (present) , … (more)
Erythroid hyperplasia (present) , Coombs-positive hemolytic anemia (present) , Short stature (present) , Reticulocytosis (present) , Hepatosplenomegaly (present) , Leukopenia (present) , Cataract (present) , Hyperpigmentation of the skin (present) , Lymphopenia (present) , Increased circulating IgM level (present) , Delayed skeletal maturation (present) (less)
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Likely pathogenic
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Anauxetic dysplasia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001576319.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in … (more)
This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 16244706, 20375313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.40G>A. ClinVar contains an entry for this variant (Variation ID: 550994). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RMRP function (PMID: 18164267). 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)
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Non-coding variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000550994). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 16244706, 20375313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.40G>A. ClinVar contains an entry for this variant (Variation ID: 550994). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RMRP function (PMID: 18164267). 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.
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:
Variant summary: RMRP n.41G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 7.7e-06 in 130626 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. n.41G>A (also known as g.40G>A) has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (Bonafe_2005, Bordon_2010). These data indicate that the variant may be associated with disease. At least one functional study reports this variant altered the structure of the P3 apical stem loop, which, in contrast to the wild type P3 domain is not efficiently bound by the Rpp20-Rpp25 heterodimer (Welting_2008). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Non-coding variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000550994). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 16244706, 20375313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.40G>A. ClinVar contains an entry for this variant (Variation ID: 550994). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RMRP function (PMID: 18164267). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygous n.64C>T mutation in mitochondrial RNA-processing endoribonuclease gene causes cartilage hair hypoplasia syndrome in two siblings. | Lugli L | European journal of medical genetics | 2021 | PMID: 33444820 |
| The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum. | Thiel CT | Best practice & research. Clinical endocrinology & metabolism | 2011 | PMID: 21396580 |
| RNase MRP and disease. | Mattijssen S | Wiley interdisciplinary reviews. RNA | 2010 | PMID: 21956908 |
| Disease-associated mutations that alter the RNA structural ensemble. | Halvorsen M | PLoS genetics | 2010 | PMID: 20808897 |
| Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation. | Bordon V | Blood | 2010 | PMID: 20375313 |
| Cartilage-hair hypoplasia-associated mutations in the RNase MRP P3 domain affect RNA folding and ribonucleoprotein assembly. | Welting TJ | Biochimica et biophysica acta | 2008 | PMID: 18164267 |
| Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. | Thiel CT | American journal of human genetics | 2007 | PMID: 17701897 |
| RNase MRP RNA and human genetic diseases. | Martin AN | Cell research | 2007 | PMID: 17189938 |
| Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. | Bonafé L | PLoS genetics | 2005 | PMID: 16244706 |
Text-mined citations for rs1156413585 ...
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 Sep 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.