VCV000689802.4 - ClinVar

NM_000977.4(RPL13):c.477+1G>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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000977.4(RPL13):c.477+1G>A

Variation ID: 689802 Accession: VCV000689802.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89562392 (GRCh38) [ NCBI UCSC ] 16: 89628800 (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	Sep 21, 2019	Jul 1, 2023	Jun 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000977.4:c.477+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001243131.1:c.336+1G>A		splice donor
NM_033251.2:c.477+1G>A		splice donor
NC_000016.10:g.89562392G>A
NC_000016.9:g.89628800G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS5DS, G-A, +1

Canonical SPDI

NC_000016.10:89562391:G:A

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

Variation affecting splicing function of RNA; Variation Ontology [ VariO:0397]

RNAseq analysis performed on a sample from this individual detected abnormal splicing of RPL13, with an alternate splice site and inclusion of additional intronic material, consistent with previous report in the literature (non-frameshift). [submitted by Undiagnosed Diseases Network, NIH]

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.

Links

OMIM: 113703.0003 dbSNP: rs1597675888 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.
RPL13		-	-	GRCh38 GRCh37	27	97

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.
Spondyloepimetaphyseal dysplasia	Pathogenic (1)	no assertion criteria provided	Mar 28, 2019	RCV000850627.1
Spondyloepimetaphyseal dysplasia, Isidor-Toutain type	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 27, 2023	RCV000991038.5

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 (May 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondyloepimetaphyseal dysplasia, Isidor-Toutain type (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal, unknown	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432138.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (1) PubMed: 31630789 Comment: This variant segregates in multiple affected individuals in the same family (proband, father, and paternal half-sister). Observation 1: Clinical Features: Wormian bones (present) , Tibial bowing (present) , Thoracic scoliosis (present) , Spondylometaphyseal dysplasia (present) , Short stature (present) , Short femoral neck (present) , … (more) Wormian bones (present) , Tibial bowing (present) , Thoracic scoliosis (present) , Spondylometaphyseal dysplasia (present) , Short stature (present) , Short femoral neck (present) , Scoliosis (present) , Platyspondyly (present) , Genu varum (present) , Flat glenoid fossa (present) , Cutis marmorata (present) , Coxa vara (present) , Acetabular dysplasia (present) , Abnormality of the vertebral column (present) , Abnormality of the lower limb (present) , Abnormality of the femoral metaphysis (present) , Abnormality of lower limb epiphysis morphology (present) , Abnormality of femoral epiphysis (present) , Abnormal form of the vertebral bodies (present) (less) Family history: yes Age: 10-19 years Sex: female Tissue: blood Segregation observed: yes Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2020-05-01 Testing laboratory interpretation: Pathogenic Observation 2: Clinical Features: Short stature (present) , Carpal bone hypoplasia (present) , Spondyloepiphyseal dysplasia (present) , Osteoarthritis (present) , Genu valgum (present) , Shallow acetabular fossae (present) , … (more) Short stature (present) , Carpal bone hypoplasia (present) , Spondyloepiphyseal dysplasia (present) , Osteoarthritis (present) , Genu valgum (present) , Shallow acetabular fossae (present) , Knee osteoarthritis (present) , Limited elbow extension and supination (present) , Aplasia/Hypoplasia of the tarsal bones (present) , Broad femoral head (present) , Flattened femoral head (present) , Hip osteoarthritis (present) , Short 3rd metacarpal (present) , Short 4th metacarpal (present) , Short 5th metacarpal (present) , Flattened femoral epiphysis (present) , Short femoral neck (present) , Abnormality of the vertebral column (present) , Irregular vertebral endplates (present) , Endplate sclerosis (present) , Intervertebral space narrowing (present) (less) Family history: yes Age: 50-59 years Sex: male Tissue: blood Segregation observed: yes Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2020-05-01 Testing laboratory interpretation: Pathogenic Observation 3: Clinical Features: Short stature (present) , Scoliosis (present) , Metatarsus adductus (present) , Lumbar hyperlordosis (present) , Small scaphoid (present) , Acetabular dysplasia (present) , Flattened femoral … (more) Short stature (present) , Scoliosis (present) , Metatarsus adductus (present) , Lumbar hyperlordosis (present) , Small scaphoid (present) , Acetabular dysplasia (present) , Flattened femoral head (present) , Short femoral neck (present) , Abnormality of pelvic girdle bone morphology (present) , Abnormality of the hip joint (present) , Coxa magna (present) (less) Family history: yes Age: 20-29 years Sex: female Tissue: blood Segregation observed: yes Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2020-05-01 Testing laboratory interpretation: Pathogenic
Pathogenic (Jun 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondyloepimetaphyseal dysplasia, Isidor-Toutain type Affected status: yes Allele origin: paternal	Rare Disease Group, Clinical Genetics, Karolinska Institutet Accession: SCV003935993.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 Comment: The c.477+1G>A variant was found de novo in an affected child with Spondyloepimetaphyseal dysplasia, Isidor-Toutain type. The variant has previously been reported multiple times to … (more) The c.477+1G>A variant was found de novo in an affected child with Spondyloepimetaphyseal dysplasia, Isidor-Toutain type. The variant has previously been reported multiple times to ClinVar (variation ID: 689802) and in the litterature, as well as functional evidence reported that the c.477+1G>A variant leads to an abnormal mRNA containing 54 bp of intron 5. (less)
Pathogenic (Mar 28, 2019)	no assertion criteria provided Method: clinical testing	Spondyloepimetaphyseal dysplasia Affected status: yes Allele origin: de novo	Bone sarcomas and remodeling of calcified tissues, INSERM Accession: SCV000992690.1 First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019	Publications: PubMed (1) PubMed: 23956136 Clinical Features: Normal birth length (present) , Early postnatal growth deficiency (present) , Severe short stature (present) , Genu varum (present) , Platyspondyly (present) , Severe epiphyseal … (more) Normal birth length (present) , Early postnatal growth deficiency (present) , Severe short stature (present) , Genu varum (present) , Platyspondyly (present) , Severe epiphyseal and metaphyseal changes for lower limbs (present) (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: literature only	SPONDYLOEPIMETAPHYSEAL DYSPLASIA, ISIDOR-TOUTAIN TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV001142142.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020	Publications: PubMed (1) PubMed: 31630789 Comment on evidence: In a male patient (P3) with the Isidor-Toutain type of spondyloepimetaphyseal dysplasia (SEMDIST; 618728), Le Caignec et al. (2019) identified heterozygosity for a de novo … (more) In a male patient (P3) with the Isidor-Toutain type of spondyloepimetaphyseal dysplasia (SEMDIST; 618728), Le Caignec et al. (2019) identified heterozygosity for a de novo splicing mutation (c.477+1G-A, NM_000977.3) in intron 5 of the RPL13 gene, leading to an 18-amino acid insertion (Asn159_Val160ins18). The mutation was not found in the ExAC/gnomAD databases. (less)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Variation affecting splicing function of RNA (VariO:0397)			Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432138.1	Publications PubMed (1) Comment: RNAseq analysis performed on a sample from this individual detected abnormal splicing of RPL13, with an alternate splice site and inclusion of additional intronic material, … (more) RNAseq analysis performed on a sample from this individual detected abnormal splicing of RPL13, with an alternate splice site and inclusion of additional intronic material, consistent with previous report in the literature (non-frameshift). (less)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.	Le Caignec C	American journal of human genetics	2019	PMID: 31630789
A new form of severe spondyloepimetaphyseal dysplasia: clinical and radiological characterization.	Isidor B	American journal of medical genetics. Part A	2013	PMID: 23956136

Text-mined citations for rs1597675888 ...

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 May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000977.4(RPL13):c.477+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1597675888 ...