VCV002691753.3 - ClinVar

NM_002139.4(RBMX):c.478CCT[2] (p.Pro162del)

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002139.4(RBMX):c.478CCT[2] (p.Pro162del)

Variation ID: 2691753 Accession: VCV002691753.3

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: Xq26.3 X: 136876558-136876560 (GRCh38) [ NCBI UCSC ] X: 135958717-135958719 (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	Feb 4, 2024	Mar 16, 2024	Mar 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002139.4:c.478CCT[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002130.2:p.Pro162del	inframe deletion
NM_002139.4:c.484_486del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_001164803.2:c.217-981CCT[2]		intron variant
NR_028476.2:n.461CCT[2]		non-coding transcript variant
NR_028477.2:n.668CCT[2]		non-coding transcript variant
NC_000023.11:g.136876559GGA[2]
NC_000023.10:g.135958718GGA[2]
NG_012918.1:g.9215CCT[2]

... more HGVS ... less HGVS

Protein change

P162del

Other names

Canonical SPDI

NC_000023.11:136876557:AGGAGGAGGA:AGGAGGA

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.

Links

OMIM: 300199.0002 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.
RBMX		-	-	GRCh38 GRCh37	22	208

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.
Severe X-linked intellectual disability, Gustavson type	Pathogenic (1)	no assertion criteria provided	Mar 13, 2024	RCV003493372.3

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 (Mar 13, 2024)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, GUSTAVSON TYPE (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV004242172.3 First in ClinVar: Feb 04, 2024 Last updated: Mar 16, 2024	Publications: PubMed (2) PubMed: 8456840‚ 37277488 Comment on evidence: In 4 affected males from a large multigenerational Swedish family with the Gustavson type of X-linked syndromic intellectual developmental disorder (MRXSG; 309555) originally reported by … (more) In 4 affected males from a large multigenerational Swedish family with the Gustavson type of X-linked syndromic intellectual developmental disorder (MRXSG; 309555) originally reported by Gustavson et al. (1993), Johansson et al. (2024) identified a hemizygous 3-bp in-frame deletion (c.484_486del, NM_002139.4) in exon 5 of the RBMX gene, resulting in the deletion of conserved residue pro162 (Pro162del) within a tri-proline structure predicted to be important for protein-protein interactions. The mutation, which was found by genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Unaffected female mutation carriers showed skewed X chromosome inactivation with silencing of the pathogenic allele. No aberrant splicing events were found in cells derived from 1 hemizygous individual or in cells transfected with the mutation. Fluorescent polarization displacement assays suggested that the mutation may adversely affect RBMX binding to SH3 domains; however, decreased SH3 affinity was only observed in short RBMX peptides (residues 156-169) and not in long peptides (residues 150-170) carrying the mutation. Furthermore, the SH3 binding residues tested (in BIN1, 601248 and ASAP1, 605953) are not likely to be the natural interaction partners of RBMX. Transcriptome analysis of neuronal cells transfected with the mutation showed a pattern of differentially expressed genes compared to controls, most notably affecting genes involved in RNA polymerase II transcription and genes encoding transcription factors. (less)

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

Title	Author	Journal	Year	Link
Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions.	Johansson J	European journal of human genetics : EJHG	2024	PMID: 37277488
New X-linked syndrome with severe mental retardation, severely impaired vision, severe hearing defect, epileptic seizures, spasticity, restricted joint mobility, and early death.	Gustavson KH	American journal of medical genetics	1993	PMID: 8456840

Text-mined citations for this variant ...

Record last updated Mar 23, 2024

ClinVar Genomic variation as it relates to human health

NM_002139.4(RBMX):c.478CCT[2] (p.Pro162del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...