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NM_170675.5(MEIS2):c.986A>G (p.Asn329Ser) AND Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 19, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002471317.1

Allele description [Variation Report for NM_170675.5(MEIS2):c.986A>G (p.Asn329Ser)]

NM_170675.5(MEIS2):c.986A>G (p.Asn329Ser)

Gene:
MEIS2:Meis homeobox 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q14
Genomic location:
Preferred name:
NM_170675.5(MEIS2):c.986A>G (p.Asn329Ser)
HGVS:
  • NC_000015.10:g.36896678T>C
  • NG_029108.1:g.209622A>G
  • NM_001220482.2:c.986A>G
  • NM_002399.4:c.947A>G
  • NM_170674.5:c.986A>G
  • NM_170675.5:c.986A>GMANE SELECT
  • NM_170676.5:c.986A>G
  • NM_170677.5:c.986A>G
  • NM_172315.3:c.947A>G
  • NM_172316.3:c.722A>G
  • NP_001207411.1:p.Asn329Ser
  • NP_002390.1:p.Asn316Ser
  • NP_733774.1:p.Asn329Ser
  • NP_733775.1:p.Asn329Ser
  • NP_733776.1:p.Asn329Ser
  • NP_733777.1:p.Asn329Ser
  • NP_758526.1:p.Asn316Ser
  • NP_758527.1:p.Asn241Ser
  • NC_000015.9:g.37188879T>C
  • NM_170675.4:c.986A>G
  • NR_051953.2:n.1992A>G
Protein change:
N241S
Molecular consequence:
  • NM_001220482.2:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002399.4:c.947A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170674.5:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170675.5:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170676.5:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170677.5:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172315.3:c.947A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172316.3:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_051953.2:n.1992A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies
Synonyms:
CLEFT PALATE, CARDIAC DEFECTS, AND IMPAIRED INTELLECTUAL DEVELOPMENT
Identifiers:
MONDO: MONDO:0010970; MedGen: C1832950; OMIM: 600987

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002767208Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Oct 19, 2020) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features.

Douglas G, Cho MT, Telegrafi A, Winter S, Carmichael J, Zackai EH, Deardorff MA, Harr M, Williams L, Psychogios A, Erwin AL, Grebe T, Retterer K, Juusola J.

Am J Med Genet A. 2018 Sep;176(9):1845-1851. doi: 10.1002/ajmg.a.40368. Epub 2018 Jul 28.

PubMed [citation]
PMID:
30055086

Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.

Verheije R, Kupchik GS, Isidor B, Kroes HY, Lynch SA, Hawkes L, Hempel M, Gelb BD, Ghoumid J, D'Amours G, Chandler K, Dubourg C, Loddo S, Tümer Z, Shaw-Smith C, Nizon M, Shevell M, Van Hoof E, Anyane-Yeboa K, Cerbone G, Clayton-Smith J, Cogné B, et al.

Eur J Hum Genet. 2019 Feb;27(2):278-290. doi: 10.1038/s41431-018-0281-5. Epub 2018 Oct 5.

PubMed [citation]
PMID:
30291340
PMCID:
PMC6336847
See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767208.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cleft palate, cardiac defects, and intellectual disability (MIM#600987). Dominant negative has been suggested as a potential mechanism of disease for missense variants (PMID: 30055086, PMID: 30291340). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This residue is a specific DNA base contact within the homeobox KN domain (NCBI, DECIPHER, PDB). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change p.(Asn329Ser) has been reported as likely pathogenic (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 5, 2023