VCV000383542.9 - ClinVar

NC_000009.12:g.35657873G>A

Germline

Classification

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.

(5)

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
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000009.12:g.35657873G>A

Variation ID: 383542 Accession: VCV000383542.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 35657873 (GRCh38) [ NCBI UCSC ] 9: 35657870 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 8, 2017	Oct 26, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_000009.12:g.35657873G>A
NC_000009.11:g.35657870G>A
NG_017041.1:g.5146C>T
NG_033120.1:g.4584G>A
LRG_163:g.5146C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000009.12:35657872:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Exome Aggregation Consortium (ExAC) 0.00009

Links

ClinGen: CA5045836 dbSNP: rs757576534 VarSome

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
Gene	OMIM	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	786	866

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jan 29, 2016	RCV000423534.2
Metaphyseal chondrodysplasia, McKusick type	Uncertain significance (1)	no assertion criteria provided	May 16, 2017	RCV000667121.2
Anauxetic dysplasia	Uncertain significance (1)	criteria provided, single submitter	Oct 8, 2022	RCV000822579.6
RMRP-related disorder	Uncertain significance (1)	no assertion criteria provided	Aug 8, 2024	RCV004748756.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2024	RCV004767257.1

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.
Likely pathogenic (Jan 29, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000523960.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: To our knowledge, the r. (146 c>t) variant in the RMRP gene, also referred to as r.(145 c>t), has not been published previously as a … (more) To our knowledge, the r. (146 c>t) variant in the RMRP gene, also referred to as r.(145 c>t), has not been published previously as a pathogenic variant nor a benign variant. This substitution occurs at a position that is conserved in mammals and changes a C:G Watson-Crick base pair to a T:G wobble base pair. In addition, other substitutions within the same stem (r.(147 g>a), r.(147 g>c), and r.(169 g>a)) have been reported in the Human Gene Mutation Database in association with CHH (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
Uncertain significance (Oct 08, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Anauxetic dysplasia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000963388.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	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 (rs757576534, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RMRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 383542). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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)
Uncertain significance (Aug 01, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005381665.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: Variant summary: RMRP n.146C>T alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00012 in 130492 control chromosomes. … (more) Variant summary: RMRP n.146C>T alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00012 in 130492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00012 vs 0.0072), allowing no conclusion about variant significance. To our knowledge, no occurrence of n.146C>T in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 383542). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (May 16, 2017)	no assertion criteria provided Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000791521.2 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Uncertain significance (Aug 08, 2024)	no assertion criteria provided Method: clinical testing	RMRP-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345390.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The RMRP n.146C>T is a noncoding alteration. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% … (more) The RMRP n.146C>T is a noncoding alteration. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

To our knowledge, the r. (146 c>t) variant in the RMRP gene, also referred to as r.(145 c>t), has not been published previously as a pathogenic variant nor a benign variant. This substitution occurs at a position that is conserved in mammals and changes a C:G Watson-Crick base pair to a T:G wobble base pair. In addition, other substitutions within the same stem (r.(147 g>a), r.(147 g>c), and r.(169 g>a)) have been reported in the Human Gene Mutation Database in association with CHH (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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 (rs757576534, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RMRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 383542). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

Variant summary: RMRP n.146C>T alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00012 in 130492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00012 vs 0.0072), allowing no conclusion about variant significance. To our knowledge, no occurrence of n.146C>T in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 383542). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The RMRP n.146C>T is a noncoding alteration. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of African descent in gnomAD. 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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs757576534 ...

These 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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NC_000009.12:g.35657873G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs757576534 ...