VCV000977819.6 - ClinVar

NM_173630.4(RTTN):c.2953A>G (p.Arg985Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_173630.4(RTTN):c.2953A>G (p.Arg985Gly)

Variation ID: 977819 Accession: VCV000977819.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q22.2 18: 70134474 (GRCh38) [ NCBI UCSC ] 18: 67801710 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 8, 2019	Sep 29, 2024	Jul 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_173630.4:c.2953A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_775901.3:p.Arg985Gly	missense
NM_001318520.2:c.217A>G	NP_001305449.1:p.Arg73Gly	missense
NC_000018.10:g.70134474T>C
NC_000018.9:g.67801710T>C
NG_033104.1:g.76253A>G

... more HGVS ... less HGVS

Protein change

R73G, R985G

Other names

Canonical SPDI

NC_000018.10:70134473:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 610436.0007 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RTTN		-	-	GRCh38 GRCh37	1218	1391

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Microcephalic primordial dwarfism due to RTTN deficiency	Pathogenic (3)	no assertion criteria provided	Jan 1, 2020	RCV001255727.5
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 5, 2023	RCV004719120.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 05, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325849.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Published RT-PCR analysis shows that this variant results in impaired splicing (Grandone et al., 2016, Vandervore et al., 2018); In silico analysis supports a deleterious … (more) Published RT-PCR analysis shows that this variant results in impaired splicing (Grandone et al., 2016, Vandervore et al., 2018); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34402213, 26940245, 30879067, 30121372) (less)
Pathogenic (Apr 03, 2019)	no assertion criteria provided Method: literature only	MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000897634.1 First in ClinVar: Apr 08, 2019 Last updated: Apr 08, 2019	Publications: PubMed (2) PubMed: 26940245‚ 30121372 Comment on evidence: In a brother and sister, born of first-cousin Moroccan parents, with microcephaly, short stature, and polymicrogyria (MSSP; 614833), Grandone et al. (2016) identified a homozygous … (more) In a brother and sister, born of first-cousin Moroccan parents, with microcephaly, short stature, and polymicrogyria (MSSP; 614833), Grandone et al. (2016) identified a homozygous T-to-C transition (chr18.6,780,1710T-C, GRCh37) at the penultimate base of exon 23 of the RTTN gene, resulting in an arg985-to-gly (R985G) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the gnomAD database. Grandone et al. (2016) showed that the mutation also led to a splicing abnormality, resulting in 2 different mRNAs, one that skipped exon 23, and the other that skipped exons 23 and 24, producing an out-of-frame messenger. In a boy, born of consanguineous Moroccan parents, with MSSP, Cavallin et al. (2018) identified homozygosity for the R985G mutation in the RTTN gene. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Microcephalic primordial dwarfism due to RTTN deficiency Affected status: yes Allele origin: unknown	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001432298.1 First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020
Pathogenic (Jan 01, 2020)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Microcephalic primordial dwarfism due to RTTN deficiency Affected status: yes Allele origin: inherited	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles Accession: SCV001481952.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021

Comment:

Published RT-PCR analysis shows that this variant results in impaired splicing (Grandone et al., 2016, Vandervore et al., 2018); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34402213, 26940245, 30879067, 30121372)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction.	Cavallin M	European journal of medical genetics	2018	PMID: 30121372
Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.	Grandone A	Clinical genetics	2016	PMID: 26940245

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_173630.4(RTTN):c.2953A>G (p.Arg985Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...