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

gnomAD frequency: 0.00004  dbSNP: rs780085174

Total submissions: 8

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)
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-10-09	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PP3, PM2_SUP
CeGaT Center for Human Genetics Tuebingen	RCV000479116	SCV005075533	likely pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MOCS2: PM3:Strong, PM2, PP3
PreventionGenetics, part of Exact Sciences	RCV004758020	SCV005360298	pathogenic	MOCS2-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The MOCS2 c.226G>A variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has also been described as c.413G>A based on alternate nomenclature outlined in Reiss and Hahnewald. 2011. PubMed ID: 21031595. This variant has been reported in the homozygous state in multiple individuals classified with severe molybdenum cofactor deficiency (Reiss and Johnson. 2003. PubMed ID: 12754701; Vijayakumar et al. 2011. PubMed ID: 21907887; Hinderhofer et al. 2017. PubMed ID: 28900816; Spiegel et al 2022. PubMed ID: 35192225). The c.226G nucleotide is the last nucleotide in exon 4 of the MOCS2 NM_004531 transcript, and the c.226G>A substitution is predicted by in silico splicing prediction programs to weaken the adjacent canonical splice donor site and increase the strength of a nearby cryptic splice donor site within exon 4, possibly leading to aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). Consistent with this observation, Reiss and Johnson reported that the c.226G>A substitution (using the c.413G>A alternate nomenclature) lead to the deletion of 4 base pairs in all MOCS2 transcripts, resulting in premature protein termination (see Table 2 in Reiss and Johnson. 2003. PubMed ID: 12754701). Based on these observations, we classify the c.226G>A (p.Gly76Arg) variant as pathogenic.