VCV000050793.41 - ClinVar

NM_213622.4(STAMBP):c.112C>T (p.Arg38Cys)

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.

(9)

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

NM_213622.4(STAMBP):c.112C>T (p.Arg38Cys)

Variation ID: 50793 Accession: VCV000050793.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.1 2: 73830968 (GRCh38) [ NCBI UCSC ] 2: 74058095 (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	Nov 23, 2014	Nov 24, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_213622.4:c.112C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_998787.1:p.Arg38Cys	missense
NM_001353967.2:c.112C>T	NP_001340896.1:p.Arg38Cys	missense
NM_001353968.2:c.112C>T	NP_001340897.1:p.Arg38Cys	missense
NM_001353969.2:c.112C>T	NP_001340898.1:p.Arg38Cys	missense
NM_001353970.2:c.112C>T	NP_001340899.1:p.Arg38Cys	missense
NM_001353971.2:c.-442C>T		5 prime UTR
NM_001353972.2:c.-203+1972C>T		intron variant
NM_001353973.2:c.-442C>T		5 prime UTR
NM_001353974.2:c.-442C>T		5 prime UTR
NM_001353975.2:c.-442C>T		5 prime UTR
NM_001353976.2:c.-442C>T		5 prime UTR
NM_006463.6:c.112C>T	NP_006454.1:p.Arg38Cys	missense
NM_201647.4:c.112C>T	NP_964010.1:p.Arg38Cys	missense
NM_213622.3:c.112C>T
NR_148668.2:n.160C>T		non-coding transcript variant
NR_148669.2:n.160C>T		non-coding transcript variant
NR_148670.2:n.340C>T		non-coding transcript variant
NR_148671.2:n.674C>T		non-coding transcript variant
NC_000002.12:g.73830968C>T
NC_000002.11:g.74058095C>T
NG_033223.2:g.7058C>T
	O95630:p.Arg38Cys

... more HGVS ... less HGVS

Protein change

R38C

Other names

NM_006463.4(STAMBP):c.112C>T(p.Arg38Cys)
NM_201647.2(STAMBP):c.112C>T(p.Arg38Cys)
NM_213622.2(STAMBP):c.112C>T(p.Arg38Cys)

Canonical SPDI

NC_000002.12:73830967:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA263227 UniProtKB: O95630#VAR_069807 OMIM: 606247.0003 dbSNP: rs143739249 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.
LOC126806253	-	-	-	GRCh38	-	35
STAMBP		-	-	GRCh38 GRCh37	167	214

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.
Microcephaly-capillary malformation syndrome	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000043574.16
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 26, 2023	RCV000426675.31

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 (Dec 30, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Microcephaly-capillary malformation syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000195120.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Pathogenic (Aug 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003271218.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 23542699 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 50793). This missense change has been observed in individual(s) with microcephaly-capillary malformation syndrome (PMID: 23542699). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs143739249, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the STAMBP protein (p.Arg38Cys). (less)
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Microcephaly-capillary malformation syndrome Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803509.1 First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016	Publications: PubMed (1) PubMed: 23542699 Comment: This variant is interpreted as a Likely Pathogenic, for Microcephaly-capillary malformation syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For … (more) This variant is interpreted as a Likely Pathogenic, for Microcephaly-capillary malformation syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:23542699). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23542699). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Supporting => PS4 downgraded in strength to Supporting (PMID:23542699). (less)
Likely pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447691.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Hypotonia (present) , Global developmental delay (present) , Plagiocephaly (present) , Developmental regression (present) , Seizure (present) Sex: male
Likely pathogenic (Jun 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517314.7 First in ClinVar: Mar 08, 2017 Last updated: Jul 01, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23542699, 32929933, 35723786, 35962715, 33149276) (less)
Pathogenic (Jul 01, 2017)	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: SCV001248156.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly-capillary malformation syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399077.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 23542699‚ 35723786 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 microcephaly-capillary malformation syndrome (MIM#614261). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated USP8 dimer domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in unrelated compound heterozygous individuals with microcephaly-capillary malformation syndrome, including one individual with this variant in trans with c.279+5G>T (DECIPHER, PMID: 23542699, 35723786). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant ( NM_213622.3:c.279+5G>T) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (May 01, 2013)	no assertion criteria provided Method: literature only	MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000071444.5 First in ClinVar: Jun 05, 2013 Last updated: Oct 09, 2016	Publications: PubMed (2) PubMed: 21815250‚ 23542699 Comment on evidence: In a boy of European descent with microcephaly-capillary malformation syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et al. (2013) identified compound heterozygous … (more) In a boy of European descent with microcephaly-capillary malformation syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et al. (2013) identified compound heterozygous mutations in the STAMBP gene: a c.112C-T transition, resulting in an arg38-to-cys (R38C) substitution, and a c.279+5G-T splice site mutation (606247.0004), predicted to include an extra codon in exon 4, supporting a pathogenic effect. The mutations, which were identified by exome sequencing and were not found in several large control exome databases, segregated with the disorder. Another patient of Polynesian descent was compound heterozygous for R38C and a 1-bp deletion (c.411delC; 606247.0007), predicted to result in a frameshift and premature termination (Ile138SerfsTer12). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Microcephaly-capillary malformation syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001739508.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Sex: female

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 50793). This missense change has been observed in individual(s) with microcephaly-capillary malformation syndrome (PMID: 23542699). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs143739249, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the STAMBP protein (p.Arg38Cys).

Comment:

This variant is interpreted as a Likely Pathogenic, for Microcephaly-capillary malformation syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:23542699). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23542699). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Supporting => PS4 downgraded in strength to Supporting (PMID:23542699).

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23542699, 32929933, 35723786, 35962715, 33149276)

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 microcephaly-capillary malformation syndrome (MIM#614261). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated USP8 dimer domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in unrelated compound heterozygous individuals with microcephaly-capillary malformation syndrome, including one individual with this variant in trans with c.279+5G>T (DECIPHER, PMID: 23542699, 35723786). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant ( NM_213622.3:c.279+5G>T) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Impact of Genetic Testing on Therapeutic Decision-Making in Childhood-Onset Epilepsies-a Study in a Tertiary Epilepsy Center.	Bayat A	Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics	2022	PMID: 35723786
Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.	McDonell LM	Nature genetics	2013	PMID: 23542699
The microcephaly-capillary malformation syndrome.	Mirzaa GM	American journal of medical genetics. Part A	2011	PMID: 21815250

Text-mined citations for rs143739249 ...

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

NM_213622.4(STAMBP):c.112C>T (p.Arg38Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143739249 ...