VCV000030949.16 - ClinVar

NM_018344.6(SLC29A3):c.1087C>T (p.Arg363Trp)

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_018344.6(SLC29A3):c.1087C>T (p.Arg363Trp)

Variation ID: 30949 Accession: VCV000030949.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.1 10: 71362267 (GRCh38) [ NCBI UCSC ] 10: 73122024 (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 4, 2013	Feb 14, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_018344.6:c.1087C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060814.4:p.Arg363Trp	missense
NM_001174098.2:c.*316C>T		3 prime UTR
NM_001363518.2:c.853C>T	NP_001350447.1:p.Arg285Trp	missense
NR_033413.2:n.1055C>T		non-coding transcript variant
NR_033414.2:n.828C>T		non-coding transcript variant
NC_000010.11:g.71362267C>T
NC_000010.10:g.73122024C>T
NG_017066.2:g.48009C>T
LRG_1318:g.48009C>T
LRG_1318t1:c.1087C>T	LRG_1318p1:p.Arg363Trp
	Q9BZD2:p.Arg363Trp

... more HGVS ... less HGVS

Protein change

R363W, R285W

Other names

Canonical SPDI

NC_000010.11:71362266: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.

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

Links

ClinGen: CA129562 UniProtKB: Q9BZD2#VAR_067807 OMIM: 612373.0011 dbSNP: rs387907067 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.
SLC29A3		-	-	GRCh38 GRCh37	479	508

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.
H syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000023939.14
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 17, 2020	RCV000493511.4
SLC29A3-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Feb 16, 2023	RCV003398566.4

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.
Likely pathogenic (Jul 17, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000582708.4 First in ClinVar: Jul 02, 2017 Last updated: Jul 24, 2021	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27143505, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27143505, 29041934, 19889517) (less)
Pathogenic (May 12, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Histiocytosis-lymphadenopathy plus syndrome Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000248907.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SLC29A3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105655.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The SLC29A3 c.1087C>T variant is predicted to result in the amino acid substitution p.Arg363Trp. This variant was reported in the homozygous state in individuals with … (more) The SLC29A3 c.1087C>T variant is predicted to result in the amino acid substitution p.Arg363Trp. This variant was reported in the homozygous state in individuals with histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (Molho-Pessach et al. 2010. PubMed ID: 19889517; Bloom et al. 2017. PubMed ID: 29041934). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-73122024-C-T). Another missense variant affecting the same amino acid residue but resulting in a different substitution (p.Arg363Gln) was also reported in the homozygous state in individuals with H syndrome (Molho-Pessach et al. 2010. PubMed ID: 19889517; Jaouadi et al. 2018. PubMed ID: 29808591). Taken together, the c.1087C>T (p.Arg363Trp) variant is interpreted as likely pathogenic. (less)
Pathogenic (Jan 04, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	H syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000954173.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 19889517‚ 27143505‚ 29041934‚ 21888995‚ 23530176‚ 27364927‚ 29808591 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 363 of the SLC29A3 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 363 of the SLC29A3 protein (p.Arg363Trp). This variant is present in population databases (rs387907067, gnomAD 0.02%). This missense change has been observed in individuals with H syndrome (PMID: 19889517, 27143505, 29041934; Invitae). ClinVar contains an entry for this variant (Variation ID: 30949). 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 SLC29A3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg363 amino acid residue in SLC29A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19889517, 21888995, 23530176, 27364927, 29808591; Invitae). 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)
Pathogenic (Jan 01, 2010)	no assertion criteria provided Method: literature only	HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045230.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 19889517 Comment on evidence: In a 20-year-old man from a consanguineous Arab family with H syndrome (602782), Molho-Pessach et al. (2010) identified homozygosity for a 1088G-A transition in exon … (more) In a 20-year-old man from a consanguineous Arab family with H syndrome (602782), Molho-Pessach et al. (2010) identified homozygosity for a 1088G-A transition in exon 6 of the SLC29A3 gene, resulting in an arg363-to-trp (R363W) substitution. (less)

Comment:

The SLC29A3 c.1087C>T variant is predicted to result in the amino acid substitution p.Arg363Trp. This variant was reported in the homozygous state in individuals with histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (Molho-Pessach et al. 2010. PubMed ID: 19889517; Bloom et al. 2017. PubMed ID: 29041934). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-73122024-C-T). Another missense variant affecting the same amino acid residue but resulting in a different substitution (p.Arg363Gln) was also reported in the homozygous state in individuals with H syndrome (Molho-Pessach et al. 2010. PubMed ID: 19889517; Jaouadi et al. 2018. PubMed ID: 29808591). Taken together, the c.1087C>T (p.Arg363Trp) variant is interpreted as likely pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 363 of the SLC29A3 protein (p.Arg363Trp). This variant is present in population databases (rs387907067, gnomAD 0.02%). This missense change has been observed in individuals with H syndrome (PMID: 19889517, 27143505, 29041934; Invitae). ClinVar contains an entry for this variant (Variation ID: 30949). 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 SLC29A3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg363 amino acid residue in SLC29A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19889517, 21888995, 23530176, 27364927, 29808591; Invitae). 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
H syndrome: Clinical, histological and genetic investigation in Tunisian patients.	Jaouadi H	The Journal of dermatology	2018	PMID: 29808591
H syndrome: 5 new cases from the United States with novel features and responses to therapy.	Bloom JL	Pediatric rheumatology online journal	2017	PMID: 29041934
H syndrome with histological features of Langerhans cell histiocytosis.	Korbi M	Indian journal of dermatology, venereology and leprology	2016	PMID: 27364927
[H syndrome: First reported paediatric case in Latin America].	Abarca Barriga HH	Revista chilena de pediatria	2016	PMID: 27143505
Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition.	Melki I	Pediatrics	2013	PMID: 23530176
Progressive hearing loss associated with a unique cervical node due to a homozygous SLC29A3 mutation: a very mild phenotype.	Jonard L	European journal of medical genetics	2012	PMID: 21888995
The H syndrome: two novel mutations affecting the same amino acid residue of hENT3.	Molho-Pessach V	Journal of dermatological science	2010	PMID: 19889517

Text-mined citations for rs387907067 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_018344.6(SLC29A3):c.1087C>T (p.Arg363Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387907067 ...