ClinVar Miner

Submissions for variant NM_004531.5(MOCS2):c.226G>A (p.Gly76Arg)

gnomAD frequency: 0.00004  dbSNP: rs780085174
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479116 SCV000568189 pathogenic not provided 2022-03-02 criteria provided, single submitter clinical testing Splice site variant of the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; in addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing, but in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 21031595, 28900816, 22403017, 12754701, 31201073, 21907887)
Invitae RCV000479116 SCV001533514 uncertain significance not provided 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 76 of the MOCS2B protein (p.Gly76Arg). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs780085174, gnomAD 0.04%). This missense change has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 12754701). ClinVar contains an entry for this variant (Variation ID: 419958). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001731709 SCV001984789 likely pathogenic Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B 2020-09-30 criteria provided, single submitter clinical testing This variant, also referred to as c.413G>A in the literature, has been previously reported in association with Molybdenum Cofactor Deficiency (PMID: 12754701, 22403017, 28900816, 21907887). The c.226G>A variant is predicted by multiple in silico tools to damage or destroy the natural splice donor site of intron 4 and create a cryptic splice donor site 4 bp upstream of the natural one. If this variant does not alter splicing, it will result in the p.Gly76Arg missense change. The c.226G>A (p.Gly76Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0044% (11/250780) and thus is presumed to be rare. This variant is located within a large region of homozygosity (ROH) seen in this patient. Based on the available evidence, the c.226G>A (p.Gly76Arg) variant is classified as Likely Pathogenic.
MGZ Medical Genetics Center RCV001731709 SCV002579812 likely pathogenic Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B 2021-12-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001731709 SCV004236374 uncertain significance Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B 2023-11-22 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001731709 SCV004244367 pathogenic Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B 2024-01-30 criteria provided, single submitter clinical testing Criteria applied: PM3_VSTR,PP3, PM2_SUP

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