VCV000014208.40 - ClinVar

NR_003051.4(RMRP):n.72A>G

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.

(18)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NR_003051.4(RMRP):n.72A>G

Variation ID: 14208 Accession: VCV000014208.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 35657948 (GRCh38) [ NCBI UCSC ] 9: 35657945 (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	Apr 4, 2013	Oct 20, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001195200.1:c.-432T>C
NR_003051.4:n.72A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		non-coding transcript variant
NC_000009.12:g.35657948T>C
NC_000009.11:g.35657945T>C
NG_017041.1:g.5071A>G
NG_033120.1:g.4659T>C
NG_116211.1:g.484T>C
LRG_163:g.5071A>G
LRG_163t1:n.71A>G

... more HGVS ... less HGVS

Protein change

Other names

70A-G
NR_003051.3:g.70A>G

Canonical SPDI

NC_000009.12:35657947:T:C

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.

1000 Genomes Project 30x 0.00016

Exome Aggregation Consortium (ExAC) 0.00047

The Genome Aggregation Database (gnomAD), exomes 0.00087

Trans-Omics for Precision Medicine (TOPMed) 0.00139

The Genome Aggregation Database (gnomAD) 0.00156

Links

ClinGen: CA257180 OMIM: 157660.0001 dbSNP: rs199476103 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.
CCDC107	-	-	-	GRCh38 GRCh37	10	111
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.
Metaphyseal dysplasia without hypotrichosis	Pathogenic (2)	no assertion criteria provided	Jan 6, 2020	RCV000015276.35
Metaphyseal chondrodysplasia, McKusick type	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000015275.40
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000313899.23
Anauxetic dysplasia	Pathogenic (1)	criteria provided, single submitter	Jan 30, 2024	RCV000555900.14
Anauxetic dysplasia 1 Metaphyseal chondrodysplasia, McKusick type Metaphyseal dysplasia without hypotrichosis	Pathogenic (1)	criteria provided, single submitter	Mar 23, 2022	RCV000763613.7
RMRP-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV003944823.3

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.
Pathogenic (Jun 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001827222.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Number of individuals with the variant: 1 Clinical Features: Metaphyseal dysplasia (present) , Tiger tail banding (present) , Midface retrusion (present) , Sparse hair (present) , Postnatal macrocephaly (present) , Depressed nasal bridge (present) … (more) Metaphyseal dysplasia (present) , Tiger tail banding (present) , Midface retrusion (present) , Sparse hair (present) , Postnatal macrocephaly (present) , Depressed nasal bridge (present) , Short stature (present) , Brittle hair (present) , Fragile nails (present) , Pectus excavatum (present) , Downslanted palpebral fissures (present) , Induced vaginal delivery (present) , Maternal hypertension (present) , Abnormal delivery (present) , Oligohydramnios (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: Causasians Tissue: blood
Pathogenic (Mar 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type Metaphyseal dysplasia without hypotrichosis Anauxetic dysplasia 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894467.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026161.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (Jan 30, 2024)	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: SCV000640120.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 16097009‚ 16838329‚ 8034306‚ 12888988‚ 10026268‚ 11207361‚ 17701897 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 (rs199476103, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16097009, 16838329). It is commonly reported in individuals of Amish ancestry (PMID: 8034306, 12888988). This variant is also known as g.70A>G. ClinVar contains an entry for this variant (Variation ID: 14208). 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 is located in a highly conserved P3 domain involved mainly in mRNA cleavage and have been reported to cause impaired cleavage of both 5.8S rRNA and cyclin B2 mRNA in transfected human fibroblast cells (PMID: 10026268, 11207361, 17701897). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 01, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329496.3 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: The RMRP gene is not translated and codes for the RNA component of a mitochondrial RNA processing endoribonuclease. The r.(71 a>g) variant has been published … (more) The RMRP gene is not translated and codes for the RNA component of a mitochondrial RNA processing endoribonuclease. The r.(71 a>g) variant has been published previously in association with cartilage-hair hypoplasia (CHH) (Ridanpaa et al., 2001; Kainulainen et al., 2014). The r.(71 a>g) variant is the most common pathogenic variant in the RMRP gene, and in the Finnish population the carrier frequency for this variant has been estimated to be as high as 1 in 76 (Sulisalo et al., 1994). This substitution occurs at a position that is conserved across species. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing (Thiel et al., 2007; Hermanns et al., 2005). Therefore, we consider this variant to be pathogenic. (less)
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362275.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 11207361‚ 17701897‚ 16254002 Comment: Variant summary: RMRP n.71A>G (noncoding transcript variant; legacy name 70A>G) is a comon pathogenic founder mutation. The variant allele was found at a frequency of … (more) Variant summary: RMRP n.71A>G (noncoding transcript variant; legacy name 70A>G) is a comon pathogenic founder mutation. The variant allele was found at a frequency of 0.00087 in 130486 control chromosomes (gnomAD). This frequency does not exceed the expected maximal pathogenic allele frequency estimated for pathogenic variants in RMRP (0.0072). n.71A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cartilage-Hair Hypoplasia (CHH; e.g. Ridanpaa_2001). These data indicate that the variant is very likely to be associated with disease. n.71A>G has been reported to impair cleavage of both 5.8S rRNA and cyclin B2 mRNA in the literature (e.g. Hermanns_2005, Thiel_2007). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014). All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194191.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (3) PubMed: 16838329‚ 12107819‚ 17701897 Comment: NR_003051.3(RMRP):c.71A>G is classified as pathogenic in the context of cartilage-hair hypoplasia. Sources cited for classification include the following: PMID 16838329, 12107819 and 17701897. Classification of … (more) NR_003051.3(RMRP):c.71A>G is classified as pathogenic in the context of cartilage-hair hypoplasia. Sources cited for classification include the following: PMID 16838329, 12107819 and 17701897. Classification of NR_003051.3(RMRP):c.71A>G is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ (less)
Pathogenic (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832468.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel
Likely pathogenic (Apr 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003925644.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: This variant was identified as compound heterozygous with NR_003051.3:n.119A>G._x000D_ Criteria applied: PS3, PM3_STR
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004234213.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondrodysplasia, McKusick type (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086982.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 8444246‚ 12107819‚ 17701897‚ 18804272 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cartilage-hair hypoplasia (MIM# 250250). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant, even intrafamilial phenotypic heterogeneity has been reported (PMID: 18804272, 8444246). (I) 0217 - Non-coding variant with known effect. Site directed mutagenesis and transfection to human fibroblasts showed that this variant impaired mildly the endonucleolytic cleavage activity of ITS-1-5.8S rRNA junction site but caused significant decrease of cyclin B2 mRNA cleavage activity (PMID: 17701897). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 350 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is the most common variant in Amish and Finnish patients with cartilage-hair hypoplasia and has been reported as pathogenic in homozygous and compound heterozygous individuals (ClinVar, PMID: 12107819). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jul 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545681.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: RMRP: PP1:Strong, PS4, PM1 Number of individuals with the variant: 1
Pathogenic (Oct 01, 2006)	no assertion criteria provided Method: literature only	CARTILAGE-HAIR HYPOPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035534.6 First in ClinVar: Apr 04, 2013 Last updated: Jun 20, 2019	Publications: PubMed (8) PubMed: 11207361‚ 9156319‚ 12888988‚ 14569119‚ 16838329‚ 16097009‚ 28094436‚ 11940090 Comment on evidence: Cartilage-Hair Hypoplasia Ridanpaa et al. (2001) identified homozygosity for an A-to-G transition at nucleotide 70 (70A-G) of the RMRP gene in 42 Finnish families with … (more) Cartilage-Hair Hypoplasia Ridanpaa et al. (2001) identified homozygosity for an A-to-G transition at nucleotide 70 (70A-G) of the RMRP gene in 42 Finnish families with cartilage-hair hypoplasia (CHH; 250250), including 12 with more than 1 affected child and 30 with a single affected child. All of these families carried modifications of the ancestral haplotype of DNA polymorphisms. In additional CHH patients, the authors identified the 70A-G mutation in compound heterozygosity with another RMRP mutation (e.g., 157660.0002). Another patient, who had been described as patient A by Sulisalo et al. (1997), had uniparental disomy for chromosome 9 with 2 copies of the maternal, 70A-G mutation-carrying chromosome, and no paternal chromosome 9. The 70A-G mutation was detected in heterozygosity in 1 of 120 Finnish control samples and in 2 of 160 non-Finnish control samples. Ridanpaa et al. (2003) reported that the most frequent, and perhaps only, mutation causing CHH in the Old Order Amish in the United States (in whom the disorder was first described) is the same 70A-G transition that is the major mutation causing CHH in Finns. They stated that although more than 40 different mutations in the RMRP gene had been characterized in other populations, 70A-G was the most common CHH-causing mutation worldwide. The mutation segregates with the same major haplotype in Finns and Amish and others, suggesting that it is very ancient. Ridanpaa et al. (2003) found homozygosity for the common Finnish mutation in 2 of 20 Canadian patients diagnosed with Schmid-type metaphyseal chondrodysplasia (156500) without the usual autosomal dominant mutation in COL10A1 (120110). The patients later developed features more typical of CHH. Hermanns et al. (2006) found the 70A-G mutation in patient number 1 of Williams et al. (2005) with CHH complicated by severe macrocytic anemia. Repeated transfusions with irradiated packed red blood cells were required. The patient remained transfusion-dependent but showed no signs of compromised immunity. The usually mild anemia of CHH is most probably self-limited. However, over half of CHH patients with severe anemia may require life-long transfusions and bone marrow transplantation (Williams et al., 2005). The so-called Finnish-Amish common transition 70A-G was observed in 12 alleles among 22 confirmed CHH patients (27%) by Hermanns et al. (2006). Klemetti et al. (2017) identified 4 Finnish patients with CHH who were compound heterozygous for the 70A-G mutation and a 10-bp duplication at posistion -13 (TACTCTGTGA) (157660.0003) in the RMRP gene. Three of the 4 had unusually mild growth failure, but evidence of significant immunodeficiency. Metaphyseal Dysplasia without Hypotrichosis In an Austrian boy with metaphyseal chondrodysplasia without hypotrichosis (MDWH; 250460), Bonafe et al. (2002) identified compound heterozygosity for mutations in the RMRP gene: the common Finnish 70A-G mutation and a 238C-T transition (157660.0009). (less)
Pathogenic (Oct 01, 2006)	no assertion criteria provided Method: literature only	METAPHYSEAL DYSPLASIA WITHOUT HYPOTRICHOSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035535.6 First in ClinVar: Apr 04, 2013 Last updated: Jun 20, 2019	Publications: PubMed (8) PubMed: 11207361‚ 9156319‚ 12888988‚ 14569119‚ 16838329‚ 16097009‚ 28094436‚ 11940090 Comment on evidence: Cartilage-Hair Hypoplasia Ridanpaa et al. (2001) identified homozygosity for an A-to-G transition at nucleotide 70 (70A-G) of the RMRP gene in 42 Finnish families with … (more) Cartilage-Hair Hypoplasia Ridanpaa et al. (2001) identified homozygosity for an A-to-G transition at nucleotide 70 (70A-G) of the RMRP gene in 42 Finnish families with cartilage-hair hypoplasia (CHH; 250250), including 12 with more than 1 affected child and 30 with a single affected child. All of these families carried modifications of the ancestral haplotype of DNA polymorphisms. In additional CHH patients, the authors identified the 70A-G mutation in compound heterozygosity with another RMRP mutation (e.g., 157660.0002). Another patient, who had been described as patient A by Sulisalo et al. (1997), had uniparental disomy for chromosome 9 with 2 copies of the maternal, 70A-G mutation-carrying chromosome, and no paternal chromosome 9. The 70A-G mutation was detected in heterozygosity in 1 of 120 Finnish control samples and in 2 of 160 non-Finnish control samples. Ridanpaa et al. (2003) reported that the most frequent, and perhaps only, mutation causing CHH in the Old Order Amish in the United States (in whom the disorder was first described) is the same 70A-G transition that is the major mutation causing CHH in Finns. They stated that although more than 40 different mutations in the RMRP gene had been characterized in other populations, 70A-G was the most common CHH-causing mutation worldwide. The mutation segregates with the same major haplotype in Finns and Amish and others, suggesting that it is very ancient. Ridanpaa et al. (2003) found homozygosity for the common Finnish mutation in 2 of 20 Canadian patients diagnosed with Schmid-type metaphyseal chondrodysplasia (156500) without the usual autosomal dominant mutation in COL10A1 (120110). The patients later developed features more typical of CHH. Hermanns et al. (2006) found the 70A-G mutation in patient number 1 of Williams et al. (2005) with CHH complicated by severe macrocytic anemia. Repeated transfusions with irradiated packed red blood cells were required. The patient remained transfusion-dependent but showed no signs of compromised immunity. The usually mild anemia of CHH is most probably self-limited. However, over half of CHH patients with severe anemia may require life-long transfusions and bone marrow transplantation (Williams et al., 2005). The so-called Finnish-Amish common transition 70A-G was observed in 12 alleles among 22 confirmed CHH patients (27%) by Hermanns et al. (2006). Klemetti et al. (2017) identified 4 Finnish patients with CHH who were compound heterozygous for the 70A-G mutation and a 10-bp duplication at posistion -13 (TACTCTGTGA) (157660.0003) in the RMRP gene. Three of the 4 had unusually mild growth failure, but evidence of significant immunodeficiency. Metaphyseal Dysplasia without Hypotrichosis In an Austrian boy with metaphyseal chondrodysplasia without hypotrichosis (MDWH; 250460), Bonafe et al. (2002) identified compound heterozygosity for mutations in the RMRP gene: the common Finnish 70A-G mutation and a 238C-T transition (157660.0009). (less)
pathologic (Mar 15, 2012)	no assertion criteria provided Method: curation	Cartilage-Hair Hypoplasia-Anauxetic Dysplasia Spectrum Disorders Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000054462.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Comment: Converted during submission to Pathogenic.
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Metaphyseal dysplasia without hypotrichosis Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142395.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NR_003051.3:n.71A>G in the RMRP gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. This variant also known as 70A>G … (more) NR_003051.3:n.71A>G in the RMRP gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. This variant also known as 70A>G in literatures, has been reported in 4/22 Cartilage-Hair Hypoplasia patients in a homozygous state and also in in compound heterozygous constellation with the transversion 262C>G in two sibs and in an unrelated patient and a compound heterozygote of the 70A>G mutant allele and the ( 14_20dup) promoter duplication(PMID: 16838329). This sequence change occurs in the RMRP gene, which encodes the RNA component of the RNase mitochondrial RNA processing (MRP) complex and does not result in a protein product. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing ( PMID: 17701897; 16838329). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP4. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Cartilage-hair hypoplasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457387.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	RMRP-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004759410.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The RMRP n.71A>G is a noncoding alteration. This variant, also known as n.70A>G in the literature, was reported in the homozygous or compound heterozygous state … (more) The RMRP n.71A>G is a noncoding alteration. This variant, also known as n.70A>G in the literature, was reported in the homozygous or compound heterozygous state in numerous individuals with RMRP-associated disorders (Ridanpää et al. 2001. PubMed ID: 11207361; Thiel et al. 2007. PubMed ID: 17701897). Functional studies showed that the n.71A>G substitution results in impaired cleavage activity and aberrant ribosomal processing (Hermanns et al. 2005. PubMed ID: 16254002; Thiel et al. 2007. PubMed ID: 17701897). This variant is reported in 0.87% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
click to load more click to collapse

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 (rs199476103, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16097009, 16838329). It is commonly reported in individuals of Amish ancestry (PMID: 8034306, 12888988). This variant is also known as g.70A>G. ClinVar contains an entry for this variant (Variation ID: 14208). 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 is located in a highly conserved P3 domain involved mainly in mRNA cleavage and have been reported to cause impaired cleavage of both 5.8S rRNA and cyclin B2 mRNA in transfected human fibroblast cells (PMID: 10026268, 11207361, 17701897). For these reasons, this variant has been classified as Pathogenic.

Comment:

The RMRP gene is not translated and codes for the RNA component of a mitochondrial RNA processing endoribonuclease. The r.(71 a>g) variant has been published previously in association with cartilage-hair hypoplasia (CHH) (Ridanpaa et al., 2001; Kainulainen et al., 2014). The r.(71 a>g) variant is the most common pathogenic variant in the RMRP gene, and in the Finnish population the carrier frequency for this variant has been estimated to be as high as 1 in 76 (Sulisalo et al., 1994). This substitution occurs at a position that is conserved across species. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing (Thiel et al., 2007; Hermanns et al., 2005). Therefore, we consider this variant to be pathogenic.

Comment:

Variant summary: RMRP n.71A>G (noncoding transcript variant; legacy name 70A>G) is a comon pathogenic founder mutation. The variant allele was found at a frequency of 0.00087 in 130486 control chromosomes (gnomAD). This frequency does not exceed the expected maximal pathogenic allele frequency estimated for pathogenic variants in RMRP (0.0072). n.71A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cartilage-Hair Hypoplasia (CHH; e.g. Ridanpaa_2001). These data indicate that the variant is very likely to be associated with disease. n.71A>G has been reported to impair cleavage of both 5.8S rRNA and cyclin B2 mRNA in the literature (e.g. Hermanns_2005, Thiel_2007). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014). All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NR_003051.3(RMRP):c.71A>G is classified as pathogenic in the context of cartilage-hair hypoplasia. Sources cited for classification include the following: PMID 16838329, 12107819 and 17701897. Classification of NR_003051.3(RMRP):c.71A>G is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cartilage-hair hypoplasia (MIM# 250250). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant, even intrafamilial phenotypic heterogeneity has been reported (PMID: 18804272, 8444246). (I) 0217 - Non-coding variant with known effect. Site directed mutagenesis and transfection to human fibroblasts showed that this variant impaired mildly the endonucleolytic cleavage activity of ITS-1-5.8S rRNA junction site but caused significant decrease of cyclin B2 mRNA cleavage activity (PMID: 17701897). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 350 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is the most common variant in Amish and Finnish patients with cartilage-hair hypoplasia and has been reported as pathogenic in homozygous and compound heterozygous individuals (ClinVar, PMID: 12107819). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

NR_003051.3:n.71A>G in the RMRP gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. This variant also known as 70A>G in literatures, has been reported in 4/22 Cartilage-Hair Hypoplasia patients in a homozygous state and also in in compound heterozygous constellation with the transversion 262C>G in two sibs and in an unrelated patient and a compound heterozygote of the 70A>G mutant allele and the ( 14_20dup) promoter duplication(PMID: 16838329). This sequence change occurs in the RMRP gene, which encodes the RNA component of the RNase mitochondrial RNA processing (MRP) complex and does not result in a protein product. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing ( PMID: 17701897; 16838329). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP4.

Comment:

The RMRP n.71A>G is a noncoding alteration. This variant, also known as n.70A>G in the literature, was reported in the homozygous or compound heterozygous state in numerous individuals with RMRP-associated disorders (Ridanpää et al. 2001. PubMed ID: 11207361; Thiel et al. 2007. PubMed ID: 17701897). Functional studies showed that the n.71A>G substitution results in impaired cleavage activity and aberrant ribosomal processing (Hermanns et al. 2005. PubMed ID: 16254002; Thiel et al. 2007. PubMed ID: 17701897). This variant is reported in 0.87% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders.	Adam MP	-	2023	PMID: 22420014
Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.	Klemetti P	Clinical genetics	2017	PMID: 28094436
Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations.	Kavadas FD	The Journal of allergy and clinical immunology	2008	PMID: 18804272
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
RMRP mutations in cartilage-hair hypoplasia.	Hermanns P	American journal of medical genetics. Part A	2006	PMID: 16838329
Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia.	Hermanns P	Human molecular genetics	2005	PMID: 16254002
The natural history of severe anemia in cartilage-hair hypoplasia.	Williams MS	American journal of medical genetics. Part A	2005	PMID: 16097009
Genetic changes in the RNA components of RNase MRP and RNase P in Schmid metaphyseal chondrodysplasia.	Ridanpää M	Journal of medical genetics	2003	PMID: 14569119
The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases.	Ridanpää M	American journal of medical genetics. Part C, Seminars in medical genetics	2003	PMID: 12888988
Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.	Ridanpää M	European journal of human genetics : EJHG	2002	PMID: 12107819
RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.	Bonafé L	Clinical genetics	2002	PMID: 11940090
Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia.	Ridanpää M	Cell	2001	PMID: 11207361
Identification of adenosine functional groups involved in substrate binding by the ribonuclease P ribozyme.	Siew D	Biochemistry	1999	PMID: 10026268
Uniparental disomy in cartilage-hair hypoplasia.	Sulisalo T	European journal of human genetics : EJHG	1997	PMID: 9156319
High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families.	Sulisalo T	Genomics	1994	PMID: 8034306
Cartilage-hair hypoplasia--clinical manifestations in 108 Finnish patients.	Mäkitie O	European journal of pediatrics	1993	PMID: 8444246
click to load more click to collapse

Text-mined citations for rs199476103 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NR_003051.4(RMRP):n.72A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199476103 ...