NM_000240.4(MAOA):c.805G>A (p.Val269Ile) AND Brunner syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001374617.7

Allele description [Variation Report for NM_000240.4(MAOA):c.805G>A (p.Val269Ile)]

NM_000240.4(MAOA):c.805G>A (p.Val269Ile)

Gene:

MAOA:monoamine oxidase A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.3

Genomic location:

Preferred name:

NM_000240.4(MAOA):c.805G>A (p.Val269Ile)

HGVS:

NC_000023.11:g.43731703G>A
NG_008957.2:g.80543G>A
NM_000240.4:c.805G>AMANE SELECT
NM_001270458.2:c.406G>A
NP_000231.1:p.Val269Ile
NP_001257387.1:p.Val136Ile
NC_000023.10:g.43590950G>A
NM_000240.3:c.805G>A

Protein change:

V136I

Links:

dbSNP: rs150176511

NCBI 1000 Genomes Browser:

rs150176511

Molecular consequence:

NM_000240.4:c.805G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270458.2:c.406G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Brunner syndrome (BRNRS)
Synonyms:: Monoamine oxidase A deficiency
Identifiers:: MONDO: MONDO:0010379; MedGen: C0796275; Orphanet: 3057; OMIM: 300615

Recent activity

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26S proteasome non-ATPase regulatory subunit 7 [Homo sapiens]
26S proteasome non-ATPase regulatory subunit 7 [Homo sapiens]
gi|25777615|ref|NP_002802.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001571463	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2021)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002199945	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001571463

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 1, 2021)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV002199945

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 17, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES, SCV001571463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

Description

The MAOA c.805G>A p.Val269Ile missense variant results in a valine to isoleucine substitution in exon 8 of 15 of the encoded protein. To our knowledge, this variant has not been previously reported in affected individuals in the literature. This variant is is observed in the Genome Aggregation Database (gnomAD) with a minor allele frequency of 0.003% (7/205,150 alleles, 0 homozygotes, 1 hemizygote) in all populations. Other pathogenic missense and truncating variants have been observed in this exon in association with Brunner syndrome. Computational prediction tools and conservation analysis provide conflicting expectations regarding an impact to protein function. This variant is classified as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002199945.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 269 of the MAOA protein (p.Val269Ile). This variant is present in population databases (rs150176511, gnomAD 0.02%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAOA protein function. ClinVar contains an entry for this variant (Variation ID: 1064570). This variant has not been reported in the literature in individuals affected with MAOA-related conditions.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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