VCV003062290.1 - ClinVar

NM_015665.6(AAAS):c.301G>T (p.Glu101Ter)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015665.6(AAAS):c.301G>T (p.Glu101Ter)

Variation ID: 3062290 Accession: VCV003062290.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 53315733 (GRCh38) [ NCBI UCSC ] 12: 53709517 (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	Mar 23, 2024	Mar 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015665.6:c.301G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056480.1:p.Glu101Ter	nonsense
NM_001173466.2:c.301G>T	NP_001166937.1:p.Glu101Ter	nonsense
NC_000012.12:g.53315733C>A
NC_000012.11:g.53709517C>A
NG_016775.1:g.10896G>T

... more HGVS ... less HGVS

Protein change

E101*

Other names

Canonical SPDI

NC_000012.12:53315732:C: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

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.
AAAS		-	-	GRCh38 GRCh38 GRCh37	480	501

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.
Glucocorticoid deficiency with achalasia	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003986012.1

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glucocorticoid deficiency with achalasia Affected status: yes Allele origin: germline	Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology Accession: SCV004801843.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: A previously undescribed nucleotide variant creates a premature translation stop signal p.Glu101Ter in the AAAS gene. The variant was observed in presumably compound heterozygous state … (more) A previously undescribed nucleotide variant creates a premature translation stop signal p.Glu101Ter in the AAAS gene. The variant was observed in presumably compound heterozygous state with a known pathogenic variant (phase not tested) in an individual affected with microcephaly. Homozygous and compound heterozygous variants are reported in patients with Achalasia-addisonianism-alacrimia syndrome, 231550. The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic. (less)

Comment:

A previously undescribed nucleotide variant creates a premature translation stop signal p.Glu101Ter in the AAAS gene. The variant was observed in presumably compound heterozygous state with a known pathogenic variant (phase not tested) in an individual affected with microcephaly. Homozygous and compound heterozygous variants are reported in patients with Achalasia-addisonianism-alacrimia syndrome, 231550. The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_015665.6(AAAS):c.301G>T (p.Glu101Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...