NM_013245.3(VPS4A):c.83C>T (p.Ala28Val) AND Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 3, 2025
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:: RCV001374867.4

Allele description [Variation Report for NM_013245.3(VPS4A):c.83C>T (p.Ala28Val)]

NM_013245.3(VPS4A):c.83C>T (p.Ala28Val)

Genes:

LOC126862382:CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:69349279-69350478 [Gene]
VPS4A:vacuolar protein sorting 4 homolog A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_013245.3(VPS4A):c.83C>T (p.Ala28Val)

HGVS:

NC_000016.10:g.69316069C>T
NM_013245.3:c.83C>TMANE SELECT
NP_037377.1:p.Ala28Val
NC_000016.9:g.69349972C>T
NM_013245.2:c.83C>T

Protein change:

A28V; ALA28VAL

Links:

OMIM: 609982.0005; dbSNP: rs1965431981

Molecular consequence:

NM_013245.3:c.83C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome
Synonyms:: CIMDAG SYNDROME; CEREBELLAR HYPOPLASIA, CATARACTS, IMPAIRED INTELLECTUAL DEVELOPMENT, CONGENITAL MICROCEPHALY, DYSTONIA, DYSERYTHROPOIETIC ANEMIA, AND GROWTH RETARDATION
Identifiers:: MONDO: MONDO:0035819; MedGen: C5543287; OMIM: 619273

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001571702	OMIM	no assertion criteria provided	Pathogenic (Jun 24, 2021)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004041549	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007611924	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 3, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33186543, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001571702

OMIM

no assertion criteria provided

Pathogenic
(Jun 24, 2021)

germline

literature only

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

SCV004041549

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 13, 2023)

unknown

clinical testing

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

SCV007611924

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 3, 2025)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects.

Seu KG, Trump LR, Emberesh S, Lorsbach RB, Johnson C, Meznarich J, Underhill HR, Chou ST, Sakthivel H, Nassar NN, Seu KJ, Blanc L, Zhang W, Lutzko CM, Kalfa TA.

Am J Hum Genet. 2020 Dec 3;107(6):1149-1156. doi: 10.1016/j.ajhg.2020.10.013. Epub 2020 Nov 12.

PubMed [citation]

PMID:: 33186543
PMCID:: PMC7820805

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, SCV001571702.1

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

Description

In a 3-year-old girl (patient 3), born of consanguineous Arab parents, with cerebellar hypoplasia, cataracts, impaired intellectual development, congenital microcephaly, dystonia, dyserythropoietic anemia, and growth retardation (CIMDAG; 619273), Seu et al. (2020) identified a homozygous c.83C-T transition (c.83C-T, NM_013245.2) in the VPS4A gene, resulting in an ala28-to-val (A28V) substitution at a conserved residue in the N-terminal MIT domain, which is important for protein binding and complex formation. The mutation, which was found by exome sequencing, segregated with the disorder in the family. Her parents, who were heterozygous for the mutation, were unaffected. It was not present in public databases, including gnomAD. Patient peripheral red blood cells showed abnormal expression of CD71 (190010), indicating impaired maturation of reticulocytes and suggesting defective endosomal sorting and trafficking of CD71. However, the hematologic disorder in this patient was not as severe as that observed in patients with heterozygous mutations.

#	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 Baylor Genetics, SCV004041549.1

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

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

From 3billion, SCV007611924.1

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

Description

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.85 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.15 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000996556 /PMID: 33186543). Therefore, this variant is classified as Likely 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 27, 2026

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