NM_018344.6(SLC29A3):c.300+1G>A AND H syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 16, 2023
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:: RCV000118377.13

Allele description [Variation Report for NM_018344.6(SLC29A3):c.300+1G>A]

NM_018344.6(SLC29A3):c.300+1G>A

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.300+1G>A

HGVS:

NC_000010.11:g.71323055G>A
NG_017066.2:g.8797G>A
NM_001174098.2:c.300+1G>A
NM_001363518.2:c.66+1G>A
NM_018344.6:c.300+1G>AMANE SELECT
LRG_1318t1:c.300+1G>A
LRG_1318:g.8797G>A
NC_000010.10:g.73082812G>A
NM_018344.5:c.300+1G>A

Nucleotide change:

IVS2, G-A, +1

Links:

OMIM: 612373.0008; dbSNP: rs587780463

NCBI 1000 Genomes Browser:

rs587780463

Molecular consequence:

NM_001174098.2:c.300+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363518.2:c.66+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_018344.6:c.300+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000045227	OMIM	no assertion criteria provided	Pathogenic (Feb 5, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9545394, 20140240
SCV000152777	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 3, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058999	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002234641	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16199547, 19336477, 20595384, 23406517, 25963354, 20140240, 27215564, 28492532

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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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness.

Moynihan LM, Bundey SE, Heath D, Jones EL, McHale DP, Mueller RF, Markham AF, Lench NJ.

Am J Hum Genet. 1998 May;62(5):1123-8.

PubMed [citation]

PMID:: 9545394
PMCID:: PMC1377081

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000045227.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 Pakistani brothers diagnosed with Faisalabad histiocytosis (602782), originally reported by Moynihan et al. (1998), Morgan et al. (2010) identified homozygosity for a +1G-A transition in intron 2 of the SLC29A3 gene. The mutation segregated with disease in the family and was not found in 384 ethnically matched control chromosomes. RT-PCR analysis of lymphocyte RNA from a heterozygous family member revealed monoallelic expression of an exon 2 coding region SNP without detection of any abnormally sized transcripts, consistent with nonsense mediated RNA decay.

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

From Genetic Services Laboratory, University of Chicago, SCV000152777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		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, SCV002058999.1

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

Description

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000130339).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000064, PM2_M). Each parent is heterozygous for the variant (PM3_P, 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, SCV002234641.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is present in population databases (rs587780463, gnomAD 0.03%). This sequence change affects a donor splice site in intron 2 of the SLC29A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC29A3 are known to be pathogenic (PMID: 19336477, 20595384, 23406517, 25963354). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 130339). Disruption of this splice site has been observed in individuals with SLC29A3-related conditions (PMID: 20140240, 27215564).

#	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: Sep 29, 2024

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