NM_018344.6(SLC29A3):c.73C>T (p.Arg25Ter) AND H syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 2, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000192336.11

Allele description [Variation Report for NM_018344.6(SLC29A3):c.73C>T (p.Arg25Ter)]

NM_018344.6(SLC29A3):c.73C>T (p.Arg25Ter)

Gene:

SLC29A3:solute carrier family 29 member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_018344.6(SLC29A3):c.73C>T (p.Arg25Ter)

HGVS:

NC_000010.11:g.71322827C>T
NG_017066.2:g.8569C>T
NM_001174098.2:c.73C>T
NM_001363518.2:c.-162C>T
NM_018344.6:c.73C>TMANE SELECT
NP_001167569.1:p.Arg25Ter
NP_060814.4:p.Arg25Ter
LRG_1318t1:c.73C>T
LRG_1318:g.8569C>T
LRG_1318p1:p.Arg25Ter
NC_000010.10:g.73082584C>T
NM_018344.5:c.73C>T
NR_033413.2:n.124C>T
NR_033414.2:n.124C>T

Protein change:

R25*

Links:

dbSNP: rs746408350

NCBI 1000 Genomes Browser:

rs746408350

Molecular consequence:

NM_001363518.2:c.-162C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_033413.2:n.124C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_033414.2:n.124C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001174098.2:c.73C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018344.6:c.73C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: H syndrome
Synonyms:: Histiocytosis with joint contractures and sensorineural deafness; Faisalabad histiocytosis; HISTIOCYTOSIS AND LYMPHADENOPATHY WITH OR WITHOUT CUTANEOUS, CARDIAC, AND/OR ENDOCRINE FEATURES, JOINT CONTRACTURES, AND/OR DEAFNESS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011273; MedGen: C1864445; Orphanet: 168569; OMIM: 602782

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000248908	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002520995	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003279941	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19336477, 20595384, 23406517, 25963354, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000248908

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 8, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002520995

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003279941

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway.

Cliffe ST, Kramer JM, Hussain K, Robben JH, de Jong EK, de Brouwer AP, Nibbeling E, Kamsteeg EJ, Wong M, Prendiville J, James C, Padidela R, Becknell C, van Bokhoven H, Deen PM, Hennekam RC, Lindeman R, Schenck A, Roscioli T, Buckley MF.

Hum Mol Genet. 2009 Jun 15;18(12):2257-65. doi: 10.1093/hmg/ddp161. Epub 2009 Mar 31.

PubMed [citation]

PMID:: 19336477

See all PubMed Citations (6)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000248908.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002520995.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with SLC29A3 related disorder (ClinVar ID: VCV000212200). The homozygous variant has been reported that each parent is heterozygous for the variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003279941.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212200). This variant has not been reported in the literature in individuals affected with SLC29A3-related conditions. This variant is present in population databases (rs746408350, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg25*) in the SLC29A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC29A3 are known to be pathogenic (PMID: 19336477, 20595384, 23406517, 25963354).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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