NM_138615.3(DHX30):c.2353C>T (p.Arg785Cys) AND Neurodevelopmental disorder with severe motor impairment and absent language

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 14, 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:: RCV000546135.10

Allele description [Variation Report for NM_138615.3(DHX30):c.2353C>T (p.Arg785Cys)]

NM_138615.3(DHX30):c.2353C>T (p.Arg785Cys)

Gene:

DHX30:DExH-box helicase 30 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_138615.3(DHX30):c.2353C>T (p.Arg785Cys)

HGVS:

NC_000003.12:g.47848246C>T
NM_001330990.2:c.2269C>T
NM_014966.4:c.2236C>T
NM_138615.3:c.2353C>TMANE SELECT
NP_001317919.1:p.Arg757Cys
NP_055781.2:p.Arg746Cys
NP_619520.1:p.Arg785Cys
NC_000003.11:g.47889736C>T
NM_138615.2:c.2353C>T

Protein change:

R746C; ARG785CYS

Links:

OMIM: 616423.0005; dbSNP: rs1085307451

NCBI 1000 Genomes Browser:

rs1085307451

Molecular consequence:

NM_001330990.2:c.2269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014966.4:c.2236C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_138615.3:c.2353C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neurodevelopmental disorder with severe motor impairment and absent language
Synonyms:: NEURODEVELOPMENTAL DISORDER WITH VARIABLE MOTOR AND LANGUAGE IMPAIRMENT
Identifiers:: MONDO: MONDO:0060622; MedGen: C4540496; OMIM: 617804

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622125	OMIM	no assertion criteria provided	Pathogenic (Feb 27, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001528539	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2018)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29100085, 25741868
SCV002605333	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175984	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 14, 2023)	unknown	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	de novo	yes	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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

Lessel D, Schob C, Küry S, Reijnders MRF, Harel T, Eldomery MK, Coban-Akdemir Z, Denecke J, Edvardson S, Colin E, Stegmann APA, Gerkes EH, Tessarech M, Bonneau D, Barth M, Besnard T, Cogné B, Revah-Politi A, Strom TM, Rosenfeld JA, Yang Y, Posey JE, et al.

Am J Hum Genet. 2017 Nov 2;101(5):716-724. doi: 10.1016/j.ajhg.2017.09.014. Erratum in: Am J Hum Genet. 2018 Jan 4;102(1):196. doi: 10.1016/j.ajhg.2017.12.016.

PubMed [citation]

PMID:: 29100085
PMCID:: PMC5673606

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, SCV000622125.3

#	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 patients (probands I, J, and K) with neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL; 617804), Lessel et al. (2017) identified a de novo heterozygous c.2353C-T transition (c.2353C-T, NM_138615.2) in the DHX30 gene, resulting in an arg785-to-cys (R785C) substitution at a highly conserved residue in motif VI within the helicase core region, which coordinates ATP binding and hydrolysis. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases.

#	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, SCV001528539.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported de novo in multiple unrelated individuals with global developmental delay, intellectual disability, severe speech impairment, gait abnormalities, cerebral atrophy, and delayed myelination [PMID 29100085]

#	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

From Suma Genomics, SCV002605333.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004175984.1

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

Description

Criteria applied: PS2_VSTR,PM2_SUP,PP2,PP3

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

Last Updated: Nov 10, 2024

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