Submissions for variant NM_000431.4(MVK):c.226+4A>G

gnomAD frequency: 0.00297  dbSNP: rs145732290

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001722201	SCV000279116	likely benign	not provided	2020-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533329	SCV000645641	benign	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2025-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001114045	SCV001271873	likely benign	Hyperimmunoglobulin D with periodic fever	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001114046	SCV001271874	likely benign	Mevalonic aciduria	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262824	SCV002542328	likely benign	Autoinflammatory syndrome	2021-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001722201	SCV004564022	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	The MVK c.226+4A>G variant (rs145732290), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234378). This variant is found in the African population with an allele frequency of 0.95% (237/24946 alleles, including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the c.226+4A>G variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences	RCV004532813	SCV004751488	benign	MVK-related disorder	2019-08-02	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).