VCV001043583.5 - ClinVar

NM_017654.4(SAMD9):c.2053C>T (p.Arg685Ter)

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.

Uncertain significance

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.2053C>T (p.Arg685Ter)

Variation ID: 1043583 Accession: VCV001043583.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.2 7: 93104045 (GRCh38) [ NCBI UCSC ] 7: 92733358 (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	Mar 22, 2021	Oct 8, 2024	Feb 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017654.4:c.2053C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060124.2:p.Arg685Ter	nonsense
NM_001193307.2:c.2053C>T	NP_001180236.1:p.Arg685Ter	nonsense
NC_000007.14:g.93104045G>A
NC_000007.13:g.92733358G>A
NG_023419.1:g.18979C>T

... more HGVS ... less HGVS

Protein change

R685*

Other names

Canonical SPDI

NC_000007.14:93104044: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.

Exome Aggregation Consortium (ExAC) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

dbSNP: rs763070754 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.
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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 12, 2024	RCV001347711.4
MIRAGE syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 17, 2022	RCV002291750.1
SAMD9-related disorder	Uncertain significance (1)	criteria provided, single submitter	Nov 4, 2022	RCV004548191.1

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.
Uncertain significance (Aug 17, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	MIRAGE syndrome Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002584561.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: The SAMD9 c.2053C>T (p.Arg685Ter) change is a nonsense variant that is predicted to cause premature protein truncation, however the functional significance of this variant is … (more) The SAMD9 c.2053C>T (p.Arg685Ter) change is a nonsense variant that is predicted to cause premature protein truncation, however the functional significance of this variant is currently unknown. This variant has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant was identified as somatic in a patient with MIRAGE syndrome and no hematological features who harbored a germline SAMD9 p.Ala722Glu variant. These variants were determined to be on the same allele, and the p.Arg685Ter functioned as a second-site reversion mutation to undo the cellular growth repression caused by the germline SAMD9 variant. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Uncertain significance (Oct 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001541985.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 26, 2023	Comment: This sequence change creates a premature translational stop signal (p.Arg685) in the SAMD9 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg685) in the SAMD9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 905 amino acid(s) of the SAMD9 protein. This variant is present in population databases (rs763070754, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SAMD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1043583). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Nov 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SAMD9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120164.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The SAMD9 c.2053C>T variant is predicted to result in premature protein termination (p.Arg685). This variant has been reported as arising de novo in an individual … (more) The SAMD9 c.2053C>T variant is predicted to result in premature protein termination (p.Arg685). This variant has been reported as arising de novo in an individual with intellectual disability (Supp. Table G in Schon et al. 2021. PubMed ID: 34732400). However, this variant is also reported in 0.026% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92733358-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Feb 12, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005332458.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Nonsense variant predicted to result in protein truncation as the last 905 amino acids are lost, in a gene for which loss of function is … (more) Nonsense variant predicted to result in protein truncation as the last 905 amino acids are lost, in a gene for which loss of function is not an established mechanism of disease; Identified as a de novo variant in a patient with suspected mitochondrial disorder; however, detailed clinical information was not provided (PMID: 34732400); This variant is associated with the following publications: (PMID: 28545555, 29175836, 34732400) (less)

Comment:

The SAMD9 c.2053C>T (p.Arg685Ter) change is a nonsense variant that is predicted to cause premature protein truncation, however the functional significance of this variant is currently unknown. This variant has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant was identified as somatic in a patient with MIRAGE syndrome and no hematological features who harbored a germline SAMD9 p.Ala722Glu variant. These variants were determined to be on the same allele, and the p.Arg685Ter functioned as a second-site reversion mutation to undo the cellular growth repression caused by the germline SAMD9 variant. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Comment:

This sequence change creates a premature translational stop signal (p.Arg685*) in the SAMD9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 905 amino acid(s) of the SAMD9 protein. This variant is present in population databases (rs763070754, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SAMD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1043583). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The SAMD9 c.2053C>T variant is predicted to result in premature protein termination (p.Arg685*). This variant has been reported as arising de novo in an individual with intellectual disability (Supp. Table G in Schon et al. 2021. PubMed ID: 34732400). However, this variant is also reported in 0.026% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92733358-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Nonsense variant predicted to result in protein truncation as the last 905 amino acids are lost, in a gene for which loss of function is not an established mechanism of disease; Identified as a de novo variant in a patient with suspected mitochondrial disorder; however, detailed clinical information was not provided (PMID: 34732400); This variant is associated with the following publications: (PMID: 28545555, 29175836, 34732400)

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs763070754 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_017654.4(SAMD9):c.2053C>T (p.Arg685Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763070754 ...