Submissions for variant NM_001358530.2(MOCS1):c.1015C>T (p.Arg339Trp)

gnomAD frequency: 0.00043  dbSNP: rs148579886

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000416188	SCV000493492	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000987692	SCV001031862	benign	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2024-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000987692	SCV001137109	likely benign	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987692	SCV001316758	uncertain significance	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002518406	SCV003612820	uncertain significance	Inborn genetic diseases	2021-02-11	criteria provided, single submitter	clinical testing	The c.1015C>T (p.R339W) alteration is located in exon 8 (coding exon 8) of the MOCS1 gene. This alteration results from a C to T substitution at nucleotide position 1015, causing the arginine (R) at amino acid position 339 to be replaced by a tryptophan (W). The p.R339W alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003907902	SCV004718157	likely benign	MOCS1-related condition	2023-10-03	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252080	SCV001427828	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354730	SCV001549416	benign	not specified		no assertion criteria provided	clinical testing	The MOCS1 p.Arg339Trp variant was not identified in the literature but was identified in dbSNP (ID: rs148579886) and ClinVar (classified as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen; classified as likely benign by Mendelics when found in combination with the p.E285K variant) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 125 of 282406 chromosomes (2 homozygous) at a frequency of 0.0004426 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 6 of 7218 chromosomes (freq: 0.000831), South Asian in 20 of 30614 chromosomes (freq: 0.000653), Latino in 23 of 35422 chromosomes (freq: 0.000649), European (non-Finnish) in 69 of 129164 chromosomes (freq: 0.000534), Ashkenazi Jewish in 4 of 10370 chromosomes (freq: 0.000386), East Asian in 1 of 19954 chromosomes (freq: 0.00005), European (Finnish) in 1 of 24706 chromosomes (freq: 0.00004), and African in 1 of 24958 chromosomes (freq: 0.00004). The p.Arg339 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.