VCV000126411.15 - ClinVar

NM_015474.4(SAMHD1):c.428G>A (p.Arg143His)

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.

(5)

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/Likely 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_015474.4(SAMHD1):c.428G>A (p.Arg143His)

Variation ID: 126411 Accession: VCV000126411.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q11.23 20: 36935110 (GRCh38) [ NCBI UCSC ] 20: 35563513 (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 24, 2015	Sep 16, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015474.4:c.428G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056289.2:p.Arg143His	missense
NM_001363729.2:c.428G>A	NP_001350658.1:p.Arg143His	missense
NM_001363733.2:c.428G>A	NP_001350662.1:p.Arg143His	missense
NC_000020.11:g.36935110C>T
NC_000020.10:g.35563513C>T
NG_017059.1:g.21734G>A
LRG_281:g.21734G>A
LRG_281t1:c.428G>A	LRG_281p1:p.Arg143His
	Q9Y3Z3:p.Arg143His

... more HGVS ... less HGVS

Protein change

R143H

Other names

Canonical SPDI

NC_000020.11:36935109:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA345521 UniProtKB: Q9Y3Z3#VAR_058483 dbSNP: rs369035155 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.
SAMHD1		-	-	GRCh38 GRCh37	824	905

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.
Aicardi-Goutieres syndrome 5	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000114352.22
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV002223787.10

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 19, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201559.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate that this variant has a damaging effect and leads to a loss of protein function (PMID: 28229507); This variant is associated … (more) Published functional studies demonstrate that this variant has a damaging effect and leads to a loss of protein function (PMID: 28229507); This variant is associated with the following publications: (PMID: 19525956, 30487145, 23364794, 22056990, 22149989, 34055681, 33683010, 27943079, 29379009, 28229507, 32371413) (less)
Pathogenic (Sep 25, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 5 Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423609.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Comment: [ACMG/AMP: PS3, PM2, PM5, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on … (more) [ACMG/AMP: PS3, PM2, PM5, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
Likely pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502603.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (5) PubMed: 19525956‚ 32371413‚ 30487145‚ 33683010‚ 28229507 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aicardi-Goutieres syndrome 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001373235.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 19525956‚ 33683010‚ 28229507‚ 29379009‚ 26431200 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the SAMHD1 protein (p.Arg143His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the SAMHD1 protein (p.Arg143His). This variant is present in population databases (rs369035155, gnomAD 0.004%). This missense change has been observed in individuals with Aicardi-Gouti√®res syndrome (PMID: 19525956, 33683010; Invitae). ClinVar contains an entry for this variant (Variation ID: 126411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SAMHD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 28229507, 29379009). This variant disrupts the p.Arg143 amino acid residue in SAMHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19525956, 26431200, 28229507). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Aicardi-Goutieres syndrome 5 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000147931.3 First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1475 BookShelf: NBK1475

Comment:

Published functional studies demonstrate that this variant has a damaging effect and leads to a loss of protein function (PMID: 28229507); This variant is associated with the following publications: (PMID: 19525956, 30487145, 23364794, 22056990, 22149989, 34055681, 33683010, 27943079, 29379009, 28229507, 32371413)

Comment:

[ACMG/AMP: PS3, PM2, PM5, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the SAMHD1 protein (p.Arg143His). This variant is present in population databases (rs369035155, gnomAD 0.004%). This missense change has been observed in individuals with Aicardi-Gouti√®res syndrome (PMID: 19525956, 33683010; Invitae). ClinVar contains an entry for this variant (Variation ID: 126411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SAMHD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 28229507, 29379009). This variant disrupts the p.Arg143 amino acid residue in SAMHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19525956, 26431200, 28229507). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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
Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.	Tise CG	American journal of medical genetics. Part A	2021	PMID: 33683010
Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.	Miller CR	Cold Spring Harbor molecular case studies	2020	PMID: 32371413
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
The SAM domain of mouse SAMHD1 is critical for its activation and regulation.	Buzovetsky O	Nature communications	2018	PMID: 29379009
A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans.	White TE	Human mutation	2017	PMID: 28229507
Aicardi-Goutières Syndrome.	Adam MP	-	2016	PMID: 20301648
Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction.	Arnold LH	PLoS pathogens	2015	PMID: 26431200
Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.	Rice GI	Nature genetics	2009	PMID: 19525956

Text-mined citations for rs369035155 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_015474.4(SAMHD1):c.428G>A (p.Arg143His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369035155 ...