Submissions for variant NM_020533.3(MCOLN1):c.1336G>A (p.Val446Met)

dbSNP: rs754097561

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489236	SCV000577355	likely pathogenic	not provided	2017-04-03	criteria provided, single submitter	clinical testing	The V446M variant has not been published as a pathogenic variant, nor has itbeen reported as a benign variant to our knowledge. The V446M variant is not observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The V446M variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. This substitution occurs at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. A missense variant at the same residue (V446L) has been reported in the HumanGene Mutation Database in association with mucolipidosis type IV (Stenson et al., 2014), supportingthe functional importance of this region of the protein. In summary, the V446M variant is likelypathogenic; however, the possibility that it is benign cannot be excluded.
Centogene AG - the Rare Disease Company	RCV000985193	SCV001426547	likely pathogenic	Mucolipidosis type IV		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985193	SCV003016584	uncertain significance	Mucolipidosis type IV	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 446 of the MCOLN1 protein (p.Val446Met). This variant is present in population databases (rs754097561, gnomAD 0.007%). This missense change has been observed in individual(s) with MCOLN1-related conditions (PMID: 32860008). ClinVar contains an entry for this variant (Variation ID: 426811). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000985193	SCV004804803	likely pathogenic	Mucolipidosis type IV	2024-03-17	criteria provided, single submitter	research
Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital	RCV000985193	SCV005088514	likely pathogenic	Mucolipidosis type IV		criteria provided, single submitter	clinical testing	The MCOLN1 variant c.1336G>A p.(Val446Met) causes an amino acid change from Val to Met at position 446 in exon(s) no. 11 (of 14). According to HGMD Professional 2024.1, this variant has previously been described as disease causing for Mucolipidosis IV (PMID:31589614, 37644014, 36937954). ClinVar lists this variant (Interpretation: Conflicting interpretations of pathogenicity; Likely pathogenic (3), Uncertain significance (1); Variation ID: 426811). The reported patients in ClinVar are majority from Arab population suggesting possible founder effect.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985193	SCV001133212	pathogenic	Mucolipidosis type IV	2019-09-26	no assertion criteria provided	clinical testing