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NM_001358530.2(MOCS1):c.1150G>A (p.Glu384Lys) AND Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

Germline classification:
Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:
Feb 25, 2024
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:
RCV000642133.17

Allele description [Variation Report for NM_001358530.2(MOCS1):c.1150G>A (p.Glu384Lys)]

NM_001358530.2(MOCS1):c.1150G>A (p.Glu384Lys)

Gene:
MOCS1:molybdenum cofactor synthesis 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p21.2
Genomic location:
Preferred name:
NM_001358530.2(MOCS1):c.1150G>A (p.Glu384Lys)
HGVS:
  • NC_000006.12:g.39909055C>T
  • NG_009297.1:g.30424G>A
  • NM_001075098.4:c.1150G>A
  • NM_001358529.2:c.1102+780G>A
  • NM_001358530.2:c.1150G>AMANE SELECT
  • NM_001358531.2:c.889G>A
  • NM_001358533.2:c.889G>A
  • NM_001358534.2:c.889G>A
  • NM_005943.6:c.1150G>A
  • NP_001068566.1:p.Gly384Ser
  • NP_001345459.1:p.Glu384Lys
  • NP_001345460.1:p.Glu297Lys
  • NP_001345462.1:p.Gly297Ser
  • NP_001345463.1:p.Gly297Ser
  • NP_005934.2:p.Gly384Ser
  • NP_005934.2:p.Gly384Ser
  • NC_000006.11:g.39876831C>T
  • NM_005943.5:c.1150G>A
  • NM_005943.6:c.1150G>A
Protein change:
E297K
Links:
dbSNP: rs751603831
NCBI 1000 Genomes Browser:
rs751603831
Molecular consequence:
  • NM_001358529.2:c.1102+780G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001075098.4:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001358530.2:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001358531.2:c.889G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001358533.2:c.889G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001358534.2:c.889G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005943.6:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A
Synonyms:
Molybdenum cofactor deficiency, complementation group A; Molybdenum Cofactor Deficiency A
Identifiers:
MONDO: MONDO:0009643; MedGen: C1854988; Orphanet: 833; OMIM: 252150

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000763786Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Aug 10, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000916139Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Uncertain significance
(Sep 6, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004101552Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significancegermlineclinical testing

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

SCV004193252Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 25, 2024)
unknownclinical testing

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

SCV004236373Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 26, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A.

Reiss J, Christensen E, Kurlemann G, Zabot MT, Dorche C.

Hum Genet. 1998 Dec;103(6):639-44.

PubMed [citation]
PMID:
9921896
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000763786.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 384 of the MOCS1 protein (p.Gly384Ser). This variant is present in population databases (rs751603831, gnomAD 0.007%). This missense change has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 9921896). ClinVar contains an entry for this variant (Variation ID: 534542). 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"). Experimental studies have shown that this missense change affects MOCS1 function (PMID: 11891227). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV000916139.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The MOCS1 c.1150G>A (p.Gly384Ser) missense variant has been reported in one study and is found in a compound heterozygous state in one individual with molybdenum cofactor deficiency (Reiss et al. 1998). The p.Gly384Ser variant was absent from 50 control chromosomes and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Expression analysis in E. coli found the p.Gly384Ser variant to have significantly reduced activity compared to wildtype (Hänzelmann et al. 2002). The p.Gly384 residue is conserved across mammals, plants, and bacteria (Reiss et al. 1998). Based on the evidence, the p.Gly384Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for molybdenum cofactor deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101552.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The missense variant in c.1150G>A(p.Glu384Lys) in MOCS1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu384Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and has an allele frequency of 0.003203% from gnomAD database. This variant has been reported to the ClinVar database as Uncertain Significance (VUS). The amino acid change p.Glu384Lys in MOCS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 384 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). The above variant has been observed in the spouse.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004193252.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV004236373.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024