Submissions for variant NM_001358530.2(MOCS1):c.418+1G>A

gnomAD frequency: 0.00006  dbSNP: rs141982812

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732511	SCV000860477	pathogenic	not provided	2018-03-19	criteria provided, single submitter	clinical testing
Invitae	RCV000006494	SCV001578437	pathogenic	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the MOCS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MOCS1 are known to be pathogenic (PMID: 12754701, 16021469). This variant is present in population databases (rs141982812, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with molybdenum cofactor deficiency (PMID: 9921896, 28274890). ClinVar contains an entry for this variant (Variation ID: 6120). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000006494	SCV002767825	pathogenic	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with molybdenum cofactor deficiency A (MIM#252150). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple compound heterozygous and homozygous patients with molybdenum cofactor deficiency (ClinVar, LOVD, PMID: 9921896, PMID: 22403017). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006494	SCV003933826	pathogenic	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: MOCS1 c.418+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 4.4e-05 in 249380 control chromosomes. c.418+1G>A has been reported in the literature in homozygotes and compound heterozygous individuals affected with Sulfite Oxidase Deficiency Due To Molybdenum Cofactor Deficiency Type A (example: Reiss_1998). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9921896). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000732511	SCV004011666	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MOCS1: PM3:Very Strong, PM2, PVS1:Moderate
Baylor Genetics	RCV000006494	SCV004193249	pathogenic	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	2024-03-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914813	SCV004735285	pathogenic	MOCS1-related disorder	2023-12-21	criteria provided, single submitter	clinical testing	The MOCS1 c.418+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported to be pathogenic for autosomal recessive molybdenum cofactor deficiency (see for example, Reiss et al. 1998. PubMed ID: 9921896; Spiegel et al. 2022. PubMed ID: 35192225). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-39893421-C-T). Variants that disrupt the consensus splice donor site in MOCS1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000006494	SCV000026677	pathogenic	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A	1999-04-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000732511	SCV001741483	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000732511	SCV001808626	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000732511	SCV001954591	likely pathogenic	not provided		no assertion criteria provided	clinical testing