VCV000253153.4 - ClinVar

NM_017654.4(SAMD9):c.3877C>T (p.Arg1293Trp)

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.

(3)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017654.4(SAMD9):c.3877C>T (p.Arg1293Trp)

Variation ID: 253153 Accession: VCV000253153.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.2 7: 93102221 (GRCh38) [ NCBI UCSC ] 7: 92731534 (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	Aug 22, 2016	Nov 25, 2023	Apr 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_017654.4:c.3877C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060124.2:p.Arg1293Trp	missense
NM_001193307.2:c.3877C>T	NP_001180236.1:p.Arg1293Trp	missense
NC_000007.14:g.93102221G>A
NC_000007.13:g.92731534G>A
NG_023419.1:g.20803C>T

... more HGVS ... less HGVS

Protein change

R1293W

Other names

Canonical SPDI

NC_000007.14:93102220:G:A

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: 610456.0004 dbSNP: rs1584251938 VarSome

Comment on variant

ClinGen staff contributed the HGVS expression for this variant.

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.
SAMD9		No evidence available	Not yet evaluated	GRCh38 GRCh37	1183	1202

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.
MIRAGE syndrome	Pathogenic (1)	no assertion criteria provided	Dec 10, 2020	RCV000239516.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 26, 2023	RCV002508782.3

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 (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818193.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Apr 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004170912.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35046037, 33423168, 27182967, 28346228, 29266745) (less)
Pathogenic (Dec 10, 2020)	no assertion criteria provided Method: literature only	MIRAGE SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000297952.1 First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 27182967 Comment on evidence: In an unrelated Japanese girl and boy who died at ages 24 months and 34 months with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) … (more) In an unrelated Japanese girl and boy who died at ages 24 months and 34 months with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) identified heterozygosity for an arg1293-to-trp (R1293W) substitution at a highly conserved residue in the SAMD9 gene. The girl died suddenly after a hospital-to-hospital transfer, whereas the boy developed monosomy 7-related myelodysplastic syndrome and died from acute respiratory distress triggered by respiratory syncytial virus infection. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples, the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R1293W mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see 602298)-positive vesicles, and RAB5A (179512) vesicles also skewed larger in patients than controls. Narumi et al. (2016) suggested that the R1293W mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35046037, 33423168, 27182967, 28346228, 29266745)

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
SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.	Narumi S	Nature genetics	2016	PMID: 27182967

Text-mined citations for rs1584251938 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 07, 2024

ClinVar Genomic variation as it relates to human health

NM_017654.4(SAMD9):c.3877C>T (p.Arg1293Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1584251938 ...