NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000413331.7

Allele description [Variation Report for NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)]

NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)

Gene:

SLC38A8:solute carrier family 38 member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q23.3

Genomic location:

Preferred name:

NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)

HGVS:

NC_000016.10:g.84017245T>G
NG_034136.1:g.29913A>C
NM_001080442.3:c.848A>CMANE SELECT
NP_001073911.1:p.Asp283Ala
NP_001073911.1:p.Asp283Ala
NC_000016.9:g.84050850T>G
NM_001080442.1:c.848A>C
NM_001080442.2:c.848A>C
p.Asp283Ala

Protein change:

D283A

Links:

dbSNP: rs139373929

NCBI 1000 Genomes Browser:

rs139373929

Molecular consequence:

NM_001080442.3:c.848A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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UPF0489 protein C5orf22 [Homo sapiens]
UPF0489 protein C5orf22 [Homo sapiens]
gi|170763486|ref|NP_060826.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000490813	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jan 26, 2016)	germline	clinical testing	Citation Link,
SCV002300948	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28546991, 29345414, 33498813, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490813

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Jan 26, 2016)

germline

clinical testing

Citation Link,

SCV002300948

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia.

Toral MA, Velez G, Boudreault K, Schaefer KA, Xu Y, Saffra N, Bassuk AG, Tsang SH, Mahajan VB.

Mol Genet Genomic Med. 2017 May;5(3):202-209. doi: 10.1002/mgg3.266.

PubMed [citation]

PMID:: 28546991
PMCID:: PMC5441399

Molecular characterization of a series of 990 index patients with albinism.

Lasseaux E, Plaisant C, Michaud V, Pennamen P, Trimouille A, Gaston L, Monfermé S, Lacombe D, Rooryck C, Morice-Picard F, Arveiler B.

Pigment Cell Melanoma Res. 2018 Jul;31(4):466-474. doi: 10.1111/pcmr.12688. Epub 2018 Feb 14.

PubMed [citation]

PMID:: 29345414

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000490813.1

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

Description

The D283A variant in the SLC38A8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D283A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D283A variant is a non-conservative amino acid substitution that occurs at a position which is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A single amino acid deletion of an adjacent residue (A282del) has been reported in the compound heterozygous state in two sisters affected with foveal hypoplasia and optic nerve decussation defects, supporting the functional importance of this region of the protein (Poulter et al., 2013). The D283A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002300948.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 283 of the SLC38A8 protein (p.Asp283Ala). This variant is present in population databases (rs139373929, gnomAD 0.6%). This missense change has been observed in individuals with autosomal recessive foveal hypoplasia (PMID: 28546991, 29345414, 33498813; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372508). 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 SLC38A8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	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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