Submissions for variant NM_001358530.2(MOCS1):c.853G>A (p.Glu285Lys)

gnomAD frequency: 0.00081  dbSNP: rs140243105

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000714706	SCV000462924	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.
CeGaT Center for Human Genetics Tuebingen	RCV000415797	SCV000493493	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714706	SCV000845431	uncertain significance	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2018-08-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000714706	SCV000895769	uncertain significance	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000714706	SCV001106980	benign	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518405	SCV003610438	uncertain significance	Inborn genetic diseases	2021-02-11	criteria provided, single submitter	clinical testing	The c.853G>A (p.E285K) alteration is located in exon 6 (coding exon 6) of the MOCS1 gene. This alteration results from a G to A substitution at nucleotide position 853, causing the glutamic acid (E) at amino acid position 285 to be replaced by a lysine (K). The p.E285K alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003907901	SCV004718065	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	RCV001252317	SCV001428069	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354513	SCV001549150	benign	not specified		no assertion criteria provided	clinical testing	The MOCS1 p.Glu285Lys variant was identified in 1 of 52 proband chromosomes (frequency: 0.019) from individuals with a known or suspected mitochondrial disorder, however the variant was suggested to be benign (Vasta_2012_PMID:22494076). The variant was identified in dbSNP (ID: rs140243105), ClinVar (classified as uncertain significance by Illumina, Fulgent Genetics, CeGaT Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences; 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 210 of 282890 chromosomes (3 homozygous) at a frequency of 0.0007423 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 8 of 7226 chromosomes (freq: 0.001107), European (non-Finnish) in 138 of 129192 chromosomes (freq: 0.001068), Latino in 37 of 35440 chromosomes (freq: 0.001044), South Asian in 20 of 30616 chromosomes (freq: 0.000653), Ashkenazi Jewish in 4 of 10370 chromosomes (freq: 0.000386), African in 2 of 24968 chromosomes (freq: 0.00008), European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Glu285 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.