VCV000183301.21 - ClinVar

NM_138422.4(ADAT3):c.430G>A (p.Val144Met)

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.

(17)

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_138422.4(ADAT3):c.430G>A (p.Val144Met)

Variation ID: 183301 Accession: VCV000183301.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 1912477 (GRCh38) [ NCBI UCSC ] 19: 1912476 (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 16, 2015	Aug 25, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_079834.4:c.-41-2502G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_138422.4:c.430G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_612431.2:p.Val144Met	missense
NM_001329533.2:c.382G>A	NP_001316462.1:p.Val128Met	missense
NM_001329539.2:c.-125-5217G>A		intron variant
NM_001329540.2:c.-41-2502G>A		intron variant
NC_000019.10:g.1912477G>A
NC_000019.9:g.1912476G>A
NG_051211.1:g.12264G>A

... more HGVS ... less HGVS

Protein change

V144M, V128M

Other names

Canonical SPDI

NC_000019.10:1912476: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA186057 OMIM: 615302.0001 dbSNP: rs730882213 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.
ADAT3		-	-	GRCh38 GRCh37	-	153
SCAMP4		-	-	GRCh38 GRCh37	22	175

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.
Intellectual disability-strabismus syndrome	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000162122.22
not provided	Pathogenic (3)	criteria provided, single submitter	Nov 25, 2023	RCV000254727.4

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426529.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020	Publications: PubMed (1) PubMed: 32860008
Pathogenic (Jun 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521996.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Mar 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability-strabismus syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Department of Biochemistry, Faculty of Medicine, University of Khartoum Accession: SCV001547514.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (2) PubMed: 23620220‚ 26842963 Comment: We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's … (more) We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's status in the patients using Sanger sequencing and detected it in a heterozygous status in their parents. Multiple reports previously classified the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) as pathogenic (Alazami et al., 2013; El-Hattab et al., 2016). (less) Sex: female
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321383.7 First in ClinVar: Oct 09, 2016 Last updated: Jul 23, 2024	Comment: Also known as p.V128M; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: … (more) Also known as p.V128M; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32860008, 31130284, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability-strabismus syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: Broad Institute Center for Mendelian Genomics (CMG) Accession: SCV000786718.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Comment: The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also … (more) The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also have mental retardation was a carrier for this variant. The p.Val144Met variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. (less) Clinical Features: Intellectual disability (present) Ethnicity/Population group: Unspecified
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996290.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 11 Ethnicity/Population group: Arab Geographic origin: Middle East
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV004099517.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Intellectual disability-strabismus syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004171164.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
Pathogenic (Jul 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022276.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability-strabismus syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804796.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Jun 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088727.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously … (more) This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously reported in patients with intellectual disability and considered as founder mutation in the Saudi Arabian population [PMID: 26842963, 23620220, 32214227]. Functional studies using cell lines derived from intellectual disability-affected individuals showed a severe reduction in tRNA deaminase activity [PMID: 31263000]. (less)
Pathogenic (Aug 01, 2019)	no assertion criteria provided Method: research	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: germline	Section for Clinical Neurogenetics, University of Tübingen Accession: SCV001156076.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (2) PubMed: 32214227‚ 23620220
Pathogenic (Jul 01, 2013)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH BRAIN ABNORMALITIES, POOR GROWTH, AND DYSMORPHIC FACIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV000082799.4 First in ClinVar: Jul 26, 2013 Last updated: Sep 12, 2021	Publications: PubMed (3) PubMed: 23620220‚ 26842963‚ 30296593 Comment on evidence: In affected members of 8 consanguineous Arab families with neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies (NEDBGF; 615286) Alazami et al. (2013) … (more) In affected members of 8 consanguineous Arab families with neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies (NEDBGF; 615286) Alazami et al. (2013) identified a homozygous c.382G-A transition in the ADAT3 gene, resulting in a val128-to-met (V128M) substitution at a highly conserved residue. Molecular modeling indicated that the mutation occurs in a hook that protrudes from the surface of the protein and would disrupt this protrusion. The mutation, which was found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families and was not found in several large control exome databases or in 580 ethnically matched alleles. Haplotype analysis indicated a founder effect, which was estimated to have occurred between 65 and 111 generations ago. Most of the patients also had esotropia and failure to thrive; some had microcephaly and mild brain malformations on MRI. In 15 affected members of 11 apparently unrelated Arab families with NEDBGF, El-Hattab et al. (2016) identified homozygosity for the same V128M founder mutation in the ADAT3 gene. El-Hattab et al. (2016) noted that all but 1 of the families with this mutation were from Saudi Arabia. Sharkia et al. (2019) identified a homozygous V128M mutation in 2 sibs, born of consanguineous Arab parents, with NEDBGF. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. (less)
Likely pathogenic (Dec 01, 2014)	no assertion criteria provided (research) Method: research	Mental retardation, autosomal recessive 36 Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000196407.1 First in ClinVar: Mar 16, 2015 Last updated: Mar 16, 2015	Publications: PubMed (1) PubMed: 25558065 Clinical Features: Intellectual disability (present) , Strabismus (present)
Pathogenic (Aug 25, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability-strabismus syndrome Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132975.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977665.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979423.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
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Comment:

We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's status in the patients using Sanger sequencing and detected it in a heterozygous status in their parents. Multiple reports previously classified the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) as pathogenic (Alazami et al., 2013; El-Hattab et al., 2016).

Comment:

Also known as p.V128M; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32860008, 31130284, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220)

Comment:

The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also have mental retardation was a carrier for this variant. The p.Val144Met variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases.

Comment:

This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously reported in patients with intellectual disability and considered as founder mutation in the Saudi Arabian population [PMID: 26842963, 23620220, 32214227]. Functional studies using cell lines derived from intellectual disability-affected individuals showed a severe reduction in tRNA deaminase activity [PMID: 31263000].

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
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.	Hengel H	European journal of human genetics : EJHG	2020	PMID: 32214227
A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome.	Sharkia R	European journal of medical genetics	2019	PMID: 30296593
ADAT3-related intellectual disability: Further delineation of the phenotype.	El-Hattab AW	American journal of medical genetics. Part A	2016	PMID: 26842963
Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus.	Alazami AM	Journal of medical genetics	2013	PMID: 23620220

Text-mined citations for rs730882213 ...

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 01, 2024

ClinVar Genomic variation as it relates to human health

NM_138422.4(ADAT3):c.430G>A (p.Val144Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730882213 ...