ClinVar Miner

Submissions for variant NM_020533.3(MCOLN1):c.694A>C (p.Thr232Pro)

gnomAD frequency: 0.00001  dbSNP: rs767122713
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000192300 SCV000951815 pathogenic Mucolipidosis type IV 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 232 of the MCOLN1 protein (p.Thr232Pro). This variant is present in population databases (rs767122713, gnomAD 0.004%). This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11317355, 20159435, 30120981). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCOLN1 protein function. Experimental studies have shown that this missense change affects MCOLN1 function (PMID: 15178326, 18794901, 28112729). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000192300 SCV001163809 likely pathogenic Mucolipidosis type IV criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192300 SCV001363132 pathogenic Mucolipidosis type IV 2019-06-14 criteria provided, single submitter clinical testing Variant summary: MCOLN1 c.694A>C (p.Thr232Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). The variant, c.694A>C, has been reported in the literature in individuals affected with Mucolipidosis Type 4 (Bargal_2001, Slaugenhaupt_2002, Geer_2010, Chaer_2018). These data indicate that the variant may be associated with disease. One publication, Dong_2008, reports this variant are shown to impair TRPML1s ability to permeate Fe2+ and residual activity is <10% of normal. One submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000192300 SCV000243821 not provided Mucolipidosis type IV no assertion provided literature only Associated with severe phenotype
Natera, Inc. RCV000192300 SCV001456128 likely pathogenic Mucolipidosis type IV 2020-09-16 no assertion criteria provided clinical testing

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