VCV000218895.12 - ClinVar

NM_001135146.2(SLC39A8):c.112G>C (p.Gly38Arg)

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

This variant is part of a Genotype

NM_022154.5(SLC39A8):c.[1019T>A];[112G>C]

Identifiers

NM_001135146.2(SLC39A8):c.112G>C (p.Gly38Arg)

Variation ID: 218895 Accession: VCV000218895.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q24 4: 102344551 (GRCh38) [ NCBI UCSC ] 4: 103265708 (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	Feb 19, 2017	Sep 29, 2024	May 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001135146.2:c.112G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001128618.1:p.Gly38Arg	missense
NM_001135147.1:c.112G>C	NP_001128619.1:p.Gly38Arg	missense
NM_022154.5:c.112G>C	NP_071437.3:p.Gly38Arg	missense
NC_000004.12:g.102344551C>G
NC_000004.11:g.103265708C>G
NG_047177.1:g.5948G>C
	Q9C0K1:p.Gly38Arg

... more HGVS ... less HGVS

Protein change

G38R

Other names

Canonical SPDI

NC_000004.12:102344550:C:G

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) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00013

Links

OMIM: 608732.0001 dbSNP: rs778210210 ClinGen: CA249424 UniProtKB: Q9C0K1#VAR_076242 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.
LOC129992876	-	-	-	GRCh38	-	25
SLC39A8		-	-	GRCh38 GRCh37	116	214

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.
SLC39A8-CDG	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 22, 2020	RCV000203234.15
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 3, 2024	RCV001386978.14

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 (Mar 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SLC39A8-CDG (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443042.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PP3_Supporting,PP3 Clinical Features: very severe ID (present) , seizures (present) , muscular hypotonia (present) , short stature (present) , strabismus (present) , cerebral atrophy (present)
Likely pathogenic (May 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SLC39A8-CDG Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023564.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001587440.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 29453449‚ 2809732‚ 26637978‚ 26637979 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC39A8 function (PMID: 29453449). Algorithms developed … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC39A8 function (PMID: 29453449). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 218895). This missense change has been observed in individuals with SLC39A8 deficiency syndrome (PMID: 2809732, 26637978, 26637979). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778210210, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 38 of the SLC39A8 protein (p.Gly38Arg). (less)
Pathogenic (May 03, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001810839.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 29, 2024	Comment: Published in vitro analysis demonstrates G38R fails to localize on the cell surface and is retained within the endoplasmic reticulum, resulting in mitochondrial dysfunction and … (more) Published in vitro analysis demonstrates G38R fails to localize on the cell surface and is retained within the endoplasmic reticulum, resulting in mitochondrial dysfunction and oxidative stress (PMID: 29453449); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27995398, 28749473, 28940310, 26637978, 26637979, 28097321, 31980526, 33163565, 34768831, 35636252, 32852845, 29453449) (less)
Pathogenic (Dec 03, 2015)	no assertion criteria provided Method: literature only	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIn Affected status: not provided Allele origin: germline	OMIM Accession: SCV000258310.2 First in ClinVar: Jan 01, 2016 Last updated: Feb 19, 2017	Publications: PubMed (2) PubMed: 26637978‚ 26637979 Comment on evidence: In 6 children of Hutterite descent and in 2 sibs, born of consanguineous Egyptian parents, with congenital disorder of glycosylation type IIn (CDG2N; 616721), Boycott … (more) In 6 children of Hutterite descent and in 2 sibs, born of consanguineous Egyptian parents, with congenital disorder of glycosylation type IIn (CDG2N; 616721), Boycott et al. (2015) identified a homozygous c.112G-C transversion (c.112G-C, NM_022154.5) in exon 1 of the SLC39A8 gene, resulting in a gly38-to-arg (G38R) substitution at a highly conserved residue within the cytoplasmic domain. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the families. It was found in heterozygous state in 2 of 15,930 alleles in the ExAC database and at low frequency among Hutterite Lehrerleut controls (1.7%) and Dariusleut (3.8%) controls. Haplotype analysis did not show a common founder effect for the Hutterite and Egyptian patients, suggesting that the mutation resulted from a recurrent event. Patient cells showed normal localization of the mutant protein, but blood levels of Zn and Mn were low and urine levels of these cations were high, suggesting renal wasting and consistent with a loss of transporter function. Functional studies of the variant were not performed. In a female infant, born of unrelated German parents, with CDG2N, Park et al. (2015) identified compound heterozygous mutations in the SLC39A8 gene: G38R and a c.1019T-A transversion in exon 6, resulting in an ile340-to-asn (I340N; 608732.0002) substitution at a highly conserved residue in transmembrane domain V, which is part of the ion channel. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The I340N variant was not found in the ExAC database. Functional studies of the variants were not performed, but the patient had no detectable serum or urinary manganese, consistent with a loss of transporter function. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC39A8 function (PMID: 29453449). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 218895). This missense change has been observed in individuals with SLC39A8 deficiency syndrome (PMID: 2809732, 26637978, 26637979). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778210210, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 38 of the SLC39A8 protein (p.Gly38Arg).

Comment:

Published in vitro analysis demonstrates G38R fails to localize on the cell surface and is retained within the endoplasmic reticulum, resulting in mitochondrial dysfunction and oxidative stress (PMID: 29453449); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27995398, 28749473, 28940310, 26637978, 26637979, 28097321, 31980526, 33163565, 34768831, 35636252, 32852845, 29453449)

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
Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders.	Choi EK	Scientific reports	2018	PMID: 29453449
SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.	Park JH	American journal of human genetics	2015	PMID: 26637979
Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.	Boycott KM	American journal of human genetics	2015	PMID: 26637978
Sacral lipoma of the filum terminale with dural arteriovenous fistula. Case report.	Djindjian M	Journal of neurosurgery	1989	PMID: 2809732

Text-mined citations for rs778210210 ...

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_001135146.2(SLC39A8):c.112G>C (p.Gly38Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs778210210 ...