VCV000242273.7 - ClinVar

NM_016824.5(ADD3):c.1100G>A (p.Gly367Asp)

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/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_016824.5(ADD3):c.1100G>A (p.Gly367Asp)

Variation ID: 242273 Accession: VCV000242273.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q25.2 10: 110122249 (GRCh38) [ NCBI UCSC ] 10: 111882007 (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	Jul 3, 2016	Mar 10, 2024	Jul 9, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_016824.5:c.1100G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_058432.1:p.Gly367Asp	missense
NM_001121.4:c.1100G>A	NP_001112.2:p.Gly367Asp	missense
NM_001320591.2:c.1100G>A	NP_001307520.1:p.Gly367Asp	missense
NM_001320592.2:c.1100G>A	NP_001307521.1:p.Gly367Asp	missense
NM_001320593.2:c.1100G>A	NP_001307522.1:p.Gly367Asp	missense
NM_001320594.2:c.866G>A	NP_001307523.1:p.Gly289Asp	missense
NM_019903.5:c.1100G>A	NP_063968.1:p.Gly367Asp	missense
NC_000010.11:g.110122249G>A
NC_000010.10:g.111882007G>A
NG_051033.1:g.130900G>A
	Q9UEY8:p.Gly367Asp

... more HGVS ... less HGVS

Protein change

G367D, G289D

Other names

Canonical SPDI

NC_000010.11:110122248:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on protein activity; Variation Ontology [ VariO:0053]

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs564185858 ClinGen: CA5686536 UniProtKB: Q9UEY8#VAR_076996 OMIM: 601568.0001 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.
ADD3		-	-	GRCh38 GRCh37	187	217

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.
Cerebral palsy, spastic quadriplegic, 3	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 9, 2020	RCV000231295.7
Cerebral palsy	Pathogenic (1)	no assertion criteria provided	-	RCV000234930.1

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 (Jun 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral palsy, spastic quadriplegic, 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443001.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: PS3, PM2, PM3, PP1_Moderate
Likely pathogenic (Jul 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral palsy, spastic quadriplegic, 3 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520238.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Apr 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral palsy, spastic quadriplegic, 3 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059435.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Pathogenic (-)	no assertion criteria provided Method: literature only	Cerebral palsy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000282045.1 First in ClinVar: Jul 10, 2016 Last updated: Jul 10, 2016	Publications: PubMed (1) PubMed: 23836506 Number of individuals with the variant: 4 Clinical Features: Frontotemporal cerebral atrophy (present) , Ventriculomegaly (present) Sex: mixed Geographic origin: Jordan
Pathogenic (Feb 15, 2024)	no assertion criteria provided Method: literature only	CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000291923.3 First in ClinVar: Jul 03, 2016 Last updated: Mar 10, 2024	Publications: PubMed (3) PubMed: 23836506‚ 30369941‚ 36046955 Comment on evidence: In 4 sibs, born of consanguineous Jordanian parents, with spastic quadriplegic cerebral palsy-3 (CPSQ3; 617008), Kruer et al. (2013) identified a homozygous c.1100G-A transition (c.1100G-A, … (more) In 4 sibs, born of consanguineous Jordanian parents, with spastic quadriplegic cerebral palsy-3 (CPSQ3; 617008), Kruer et al. (2013) identified a homozygous c.1100G-A transition (c.1100G-A, ENST00000356080) in the ADD3 gene, resulting in a gly367-to-asp (G367D) substitution in the putative oligomerization domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in 208 ethnically matched Middle Eastern controls and 450 mixed European controls. Lysates from patient fibroblasts showed a significant increase in actin polymerization compared to controls, consistent with impaired actin capping activity and a loss of function. Knockdown of the ADD3 transcript using siRNA resulted in similarly impaired actin capping. Compared to controls, mutant fibroblast showed a lack of neurite-like processes and increased proliferation and migration. The mutation also impaired the ability of mutant ADD3 to associate with the ADD1 (102680) subunit. Overall, the biologic studies implicated abnormalities of components of the dynamic cytoskeleton and process outgrowth in neuromotor dysfunction. By whole-exome sequencing in a patient, born to consanguineous parents, with CPSQ3, Theunissen et al. (2018) identified homozygosity for the G367D mutation in the ADD3 gene. Functional studies in patient cells were not performed. In a Syrian patient, born to consanguineous parents, with CPSQ3, Sanchez Marco et al. (2022) identified homozygosity for the G367D mutation in the ADD3 gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. (less)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on protein activity	Method not provided	Result not provided	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000282045.1	Publications PubMed (1)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hereditary spastic paraparesis presenting as cerebral palsy due to ADD3 variant with mechanistic insight provided by a Drosophila γ-adducin model.	Sanchez Marco SB	Clinical genetics	2022	PMID: 36046955
Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause.	Theunissen TEJ	Frontiers in genetics	2018	PMID: 30369941
Mutations in γ adducin are associated with inherited cerebral palsy.	Kruer MC	Annals of neurology	2013	PMID: 23836506

Text-mined citations for rs564185858 ...

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 Mar 11, 2024

ClinVar Genomic variation as it relates to human health

NM_016824.5(ADD3):c.1100G>A (p.Gly367Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs564185858 ...