VCV000011492.11 - ClinVar

NM_006579.3(EBP):c.440G>A (p.Arg147His)

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.

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_006579.3(EBP):c.440G>A (p.Arg147His)

Variation ID: 11492 Accession: VCV000011492.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 48527256 (GRCh38) [ NCBI UCSC ] X: 48385644 (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	Sep 30, 2023	Sep 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006579.3:c.440G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006570.1:p.Arg147His	missense
NC_000023.11:g.48527256G>A
NC_000023.10:g.48385644G>A
NG_007452.1:g.10481G>A
	Q15125:p.Arg147His

... more HGVS ... less HGVS

Protein change

R147H

Other names

Canonical SPDI

NC_000023.11:48527255: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.

Links

ClinGen: CA255907 UniProtKB: Q15125#VAR_012108 OMIM: 300205.0012 dbSNP: rs28935174 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.
EBP		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	179	347

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.
Chondrodysplasia punctata 2 X-linked dominant	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000012247.22
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 22, 2023	RCV003329229.1

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.
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Chondrodysplasia punctata, X-linked dominant (X-linked inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000193078.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chondrodysplasia punctata 2 X-linked dominant (X-linked inheritance) Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053793.2 First in ClinVar: Jan 08, 2022 Last updated: Jul 17, 2022	Publications: PubMed (1) PubMed: 10942423 Number of individuals with the variant: 1 Family history: yes Secondary finding: no Method: Exome sequencing
Pathogenic (Sep 22, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004036915.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023	Comment: Female patient witth this variant showed accumulation of 8(9)-cholesterol and 8-dehydrocholesterol by GC/MS, suggestive of a defect of sterol-delta8-isomerase, and subsequent functional studies showed that … (more) Female patient witth this variant showed accumulation of 8(9)-cholesterol and 8-dehydrocholesterol by GC/MS, suggestive of a defect of sterol-delta8-isomerase, and subsequent functional studies showed that this variant partially impairs enzyme activity (Braverman et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11982764, 22121851, 10391219, 7677157, 1355069, 11493318, 25814754, 22229330, 12824059, 12509714, 27276700, 14632217, 12483303, 11038443, 17625999, 19416264, 31299979, 30608402, 10942423, 34450268, SunMA2023[Article]) (less)
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chondrodysplasia punctata 2 X-linked dominant Affected status: yes Allele origin: germline	3billion Accession: SCV002521099.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (7) PubMed: 1355069‚ 12483303‚ 7677157‚ 11493318‚ 10942423‚ 24726177‚ 26075358 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011492). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:10942423, 12483303, 1355069, 24726177, 7677157). Different missense changes at the same codon (p.Arg147Cys, p.Arg147Gly) have been reported to be associated with EBP related disorder (ClinVar ID: VCV000265110 / PMID: 11493318, 26075358). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cupped ear (present) , Retrognathia (present) , Thoracic scoliosis (present) , Short neck (present) , Protuberant abdomen (present) , Skin dimple over apex of long … (more) Cupped ear (present) , Retrognathia (present) , Thoracic scoliosis (present) , Short neck (present) , Protuberant abdomen (present) , Skin dimple over apex of long bone angulation (present) , Pectus excavatum (present) , Asymmetry of the thorax (present) , Abnormality of skin pigmentation (present) , Distributed along Blaschko lines (present) , Torticollis (present) (less)
Pathogenic (Jan 01, 2003)	no assertion criteria provided Method: literature only	CHONDRODYSPLASIA PUNCTATA 2, X-LINKED DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032481.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 10942423‚ 12483303‚ 7677157‚ 1355069 Comment on evidence: Has et al. (2000) described a family in which 2 children with CDPX2 (302960) had an arg147-to-his (R147H) mutation of the EBP gene but showed … (more) Has et al. (2000) described a family in which 2 children with CDPX2 (302960) had an arg147-to-his (R147H) mutation of the EBP gene but showed differing severity of the disease. Shirahama et al. (2003) described a patient with the same mutation, caused by a 440G-A transition in exon 4, which was also found in her clinically unaffected mother. Expression analysis demonstrated that the mutant allele was predominantly expressed in the patient, while both alleles were expressed in her mother. Methylation analysis revealed that the wildtype allele was predominantly inactivated in the patient, while the mutated allele was predominantly inactivated in her mother. Thus, differences in expression of the mutated allele caused by skewed X-chromosome inactivation produced the diverse phenotypes within this family. Shirahama et al. (2003) noted that anticipation was a striking clinical feature of CDPX2 in the studies of Sutphen et al. (1995) and Traupe et al. (1992) and suggested that skewed methylation may have a role in this phenomenon. (less)

Comment:

Female patient witth this variant showed accumulation of 8(9)-cholesterol and 8-dehydrocholesterol by GC/MS, suggestive of a defect of sterol-delta8-isomerase, and subsequent functional studies showed that this variant partially impairs enzyme activity (Braverman et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11982764, 22121851, 10391219, 7677157, 1355069, 11493318, 25814754, 22229330, 12824059, 12509714, 27276700, 14632217, 12483303, 11038443, 17625999, 19416264, 31299979, 30608402, 10942423, 34450268, SunMA2023[Article])

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011492). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:10942423, 12483303, 1355069, 24726177, 7677157). Different missense changes at the same codon (p.Arg147Cys, p.Arg147Gly) have been reported to be associated with EBP related disorder (ClinVar ID: VCV000265110 / PMID: 11493318, 26075358). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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
Keratotic follicular plugs with calcifications in Conradi-Hünermann-Happle syndrome: histological, biochemical and genetic testing correlation.	Leclerc-Mercier S	The British journal of dermatology	2015	PMID: 26075358
Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.	Morrone A	Molecular genetics and metabolism	2014	PMID: 24726177
Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata.	Shirahama S	Human genetics	2003	PMID: 12483303
Identification of a novel mutation in 3beta-hydroxysteroid-Delta8-Delta7-isomerase in a case of Conradi-Hünermann-Happle syndrome.	Becker K	Experimental dermatology	2001	PMID: 11493318
The Conradi-Hünermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism.	Has C	Human molecular genetics	2000	PMID: 10942423
XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome).	Sutphen R	American journal of medical genetics	1995	PMID: 7677157
Exclusion mapping of the X-linked dominant chondrodysplasia punctata/ichthyosis/cataract/short stature (Happle) syndrome: possible involvement of an unstable pre-mutation.	Traupe H	Human genetics	1992	PMID: 1355069

Text-mined citations for rs28935174 ...

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 Feb 14, 2024

ClinVar Genomic variation as it relates to human health

NM_006579.3(EBP):c.440G>A (p.Arg147His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28935174 ...