NM_001135146.2(SLC39A8):c.610G>T (p.Gly204Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jun 2, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000733882.34

Allele description [Variation Report for NM_001135146.2(SLC39A8):c.610G>T (p.Gly204Cys)]

NM_001135146.2(SLC39A8):c.610G>T (p.Gly204Cys)

Gene:

SLC39A8:solute carrier family 39 member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q24

Genomic location:

Preferred name:

NM_001135146.2(SLC39A8):c.610G>T (p.Gly204Cys)

HGVS:

NC_000004.12:g.102305054C>A
NG_047177.1:g.45445G>T
NM_001135146.2:c.610G>TMANE SELECT
NM_001135147.1:c.610G>T
NM_001135148.2:c.409G>T
NM_022154.5:c.610G>T
NP_001128618.1:p.Gly204Cys
NP_001128619.1:p.Gly204Cys
NP_001128620.1:p.Gly137Cys
NP_071437.3:p.Gly204Cys
NC_000004.11:g.103226211C>A
NC_000004.11:g.103226211C>A
Q9C0K1:p.Gly204Cys

Protein change:

G137C; GLY204CYS

Links:

UniProtKB: Q9C0K1#VAR_076243; OMIM: 608732.0004; dbSNP: rs779241085

NCBI 1000 Genomes Browser:

rs779241085

Molecular consequence:

NM_001135146.2:c.610G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001135147.1:c.610G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001135148.2:c.409G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022154.5:c.610G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000861985	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Jun 26, 2018)	germline	clinical testing	Citation Link,
SCV001154211	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2016)	germline	clinical testing	Citation Link,
SCV001988967	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 2, 2023)	germline	clinical testing	Citation Link,
SCV002501593	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26637979, 29453449, 25741868
SCV003525522	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 19, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26637979, 34768831, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders.

Choi EK, Nguyen TT, Gupta N, Iwase S, Seo YA.

Sci Rep. 2018 Feb 16;8(1):3163. doi: 10.1038/s41598-018-21464-0.

PubMed [citation]

PMID:: 29453449
PMCID:: PMC5816659

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

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000861985.1

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

#	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		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001154211.21

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV001988967.4

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

Description

Published functional studies suggest a damaging effect (Choi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28557351, 30090406, 28749473, 29453449, 32753748, 26637979, 34768831)

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	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		1	not provided	not provided	not provided

From Invitae, SCV003525522.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 204 of the SLC39A8 protein (p.Gly204Cys). This variant is present in population databases (rs779241085, gnomAD 0.01%). This missense change has been observed in individual(s) with SLC39A8-congenital disorder of glycosylation (PMID: 26637979). ClinVar contains an entry for this variant (Variation ID: 218897). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SLC39A8 function (PMID: 34768831). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Apr 20, 2024

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