NM_014975.3(MAST1):c.1549G>A (p.Gly517Ser) AND Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 20, 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:: RCV000735992.4

Allele description [Variation Report for NM_014975.3(MAST1):c.1549G>A (p.Gly517Ser)]

NM_014975.3(MAST1):c.1549G>A (p.Gly517Ser)

Gene:

MAST1:microtubule associated serine/threonine kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_014975.3(MAST1):c.1549G>A (p.Gly517Ser)

HGVS:

NC_000019.10:g.12865089G>A
NG_054729.1:g.36159G>A
NM_014975.3:c.1549G>AMANE SELECT
NP_055790.1:p.Gly517Ser
NC_000019.9:g.12975903G>A
NM_014975.2:c.1549G>A

Protein change:

G517S; GLY517SER

Links:

OMIM: 612256.0004; dbSNP: rs1568413207

NCBI 1000 Genomes Browser:

rs1568413207

Molecular consequence:

NM_014975.3:c.1549G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations
Identifiers:: MONDO: MONDO:0032648; MedGen: C4748927; OMIM: 618273

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000864196	OMIM	no assertion criteria provided	Pathogenic (Jan 10, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002011921	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30449657, 25741868
SCV003918978	Duke University Health System Sequencing Clinic, Duke University Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2023)	de novo	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000864196

OMIM

no assertion criteria provided

Pathogenic
(Jan 10, 2019)

germline

literature only

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

SCV002011921

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003918978

Duke University Health System Sequencing Clinic, Duke University Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 20, 2023)

de novo

research

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	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations.

Tripathy R, Leca I, van Dijk T, Weiss J, van Bon BW, Sergaki MC, Gstrein T, Breuss M, Tian G, Bahi-Buisson N, Paciorkowski AR, Pagnamenta AT, Wenninger-Weinzierl A, Martinez-Reza MF, Landler L, Lise S, Taylor JC, Terrone G, Vitiello G, Del Giudice E, Brunetti-Pierri N, D'Amico A, et al.

Neuron. 2018 Dec 19;100(6):1354-1368.e5. doi: 10.1016/j.neuron.2018.10.044. Epub 2018 Nov 15.

PubMed [citation]

PMID:: 30449657
PMCID:: PMC6436622

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

Details of each submission

From OMIM, SCV000864196.1

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

Description

In 3 unrelated girls (patients 4, 5, and 6) with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM; 618273), Tripathy et al. (2018) identified a de novo heterozygous c.1549G-A transition in the MAST1 gene, resulting in a gly517-to-ser (G517S) substitution at a conserved residue in the kinase domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional studies showed that the variant only slightly increased the interaction of MAST1 with microtubules.

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

From 3billion, SCV002011921.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (ClinVar ID: VCV000599361.3, PMID: 30449657, PS2 and PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.822, 3Cnet: 0.994, PP3). Patient's phenotype is considered compatible with Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Duke University Health System Sequencing Clinic, Duke University Health System, SCV003918978.1

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

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

Last Updated: May 19, 2024

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