VCV000039732.6 - ClinVar

NM_024666.5(AAGAB):c.481C>T (p.Arg161Ter)

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.

(3)

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_024666.5(AAGAB):c.481C>T (p.Arg161Ter)

Variation ID: 39732 Accession: VCV000039732.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 67231868 (GRCh38) [ NCBI UCSC ] 15: 67524206 (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	Feb 14, 2024	Nov 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_024666.5:c.481C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078942.3:p.Arg161Ter	nonsense
NM_001271885.2:c.154C>T	NP_001258814.1:p.Arg52Ter	nonsense
NM_001271886.2:c.154C>T	NP_001258815.1:p.Arg52Ter	nonsense
NC_000015.10:g.67231868G>A
NC_000015.9:g.67524206G>A
NG_033007.1:g.28331C>T

... more HGVS ... less HGVS

Protein change

R161*, R52*

Other names

Canonical SPDI

NC_000015.10:67231867: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA7627086 OMIM: 614888.0001 dbSNP: rs746488412 VarSome

Comment on variant

ClinGen staff contributed the HGVS expression for this variant.

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.
AAGAB		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	77	115

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.
Palmoplantar keratoderma, punctate type 1A	Pathogenic (2)	criteria provided, single submitter	Jan 3, 2022	RCV000032947.6
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 4, 2022	RCV003556096.2

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 (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Palmoplantar keratoderma, punctate type 1A Affected status: yes Allele origin: germline	3billion Accession: SCV002058339.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:23000146 PMID:23000146 Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). The variant has been reported to be associated with AAGAB related disorder (ClinVar ID: VCV000039732, PMID:23000146). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Palmoplantar keratoderma (present)
Pathogenic (Nov 04, 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: SCV004297628.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 23000146‚ 23064416‚ 23563198‚ 23633024‚ 24390136 Comment: This variant is present in population databases (rs746488412, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg161) in the AAGAB gene. It … (more) This variant is present in population databases (rs746488412, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg161) in the AAGAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAGAB are known to be pathogenic (PMID: 23000146, 23064416, 23563198, 23633024, 24390136). This premature translational stop signal has been observed in individual(s) with punctate palmoplantar keratoderma, type Buschke-Fischer-Brauer (PMID: 23000146). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39732). (less)
Pathogenic (Nov 01, 2012)	no assertion criteria provided Method: literature only	KERATODERMA, PALMOPLANTAR, PUNCTATE TYPE IA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056719.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2019	Publications: PubMed (2) PubMed: 23000146‚ 23064416 Comment on evidence: In affected members of 2 Croatian families with type I punctate palmoplantar keratoderma (PPKP1A; 148600), Giehl et al. (2012) identified heterozygosity for a 481C-T transition … (more) In affected members of 2 Croatian families with type I punctate palmoplantar keratoderma (PPKP1A; 148600), Giehl et al. (2012) identified heterozygosity for a 481C-T transition in exon 5 of the AAGAB gene, resulting in an arg161-to-ter (R161X) substitution. The mutation was not found in unaffected family members. Genotyping of 21 individuals from the 2 families revealed a 1.2-Mb common haplotype between markers SNP15-67469128 and SNP15-68728632, indicating that the affected individuals inherited the mutation by descent from a common ancestor. Immunoblot analysis confirmed the predicted truncated size of approximately 24 kD for R161X and showed a strong band, suggesting that the protein is stable and not degraded. Allele-specific PCR amplification yielded only a very small peak for the 481C-T allele. In a 4-generation Scottish family with PPKP, Pohler et al. (2012) identified heterozygosity for the R161X mutation, which segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases. (less)

Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). The variant has been reported to be associated with AAGAB related disorder (ClinVar ID: VCV000039732, PMID:23000146). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant is present in population databases (rs746488412, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg161*) in the AAGAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAGAB are known to be pathogenic (PMID: 23000146, 23064416, 23563198, 23633024, 24390136). This premature translational stop signal has been observed in individual(s) with punctate palmoplantar keratoderma, type Buschke-Fischer-Brauer (PMID: 23000146). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39732).

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
Identification of distinct mutations in AAGAB in families with type 1 punctate palmoplantar keratoderma.	Furniss M	The Journal of investigative dermatology	2014	PMID: 24390136
Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients.	Cui H	The Journal of investigative dermatology	2013	PMID: 23633024
Novel and recurrent AAGAB mutations: clinical variability and molecular consequences.	Kiritsi D	The Journal of investigative dermatology	2013	PMID: 23563198
Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.	Pohler E	Nature genetics	2012	PMID: 23064416
Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.	Giehl KA	American journal of human genetics	2012	PMID: 23000146

Text-mined citations for rs746488412 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_024666.5(AAGAB):c.481C>T (p.Arg161Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs746488412 ...