Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000194491 | SCV001338200 | likely pathogenic | Mucolipidosis type IV | 2024-03-25 | criteria provided, single submitter | clinical testing | Variant summary: MCOLN1 c.1336G>T (p.Val446Leu) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein sequence. Three 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 251458 control chromosomes (gnomAD). c.1336G>T has been reported in the literature in at least one homozygous individual from a consanguineous family affected with Mucolipidosis Type 4 (Sun_2000). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in resistance to the inhibition of ion channel activity at low pH (Roychowdhury_2004), significantly reduced co-localization to lysosomes (Chen_2014), and impaired cationic iron permeability resulting in <10% of normal activity (Dong_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11030752, 18794901, 14749347, 25119295). ClinVar contains an entry for this variant (Variation ID: 208033). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV001266563 | SCV001444739 | likely pathogenic | Inborn genetic diseases | 2020-02-04 | criteria provided, single submitter | clinical testing | The alteration results in an amino acid change:_x000D_ _x000D_ The c.1336G>T (p.V446L) alteration is located in coding exon 11 of the MCOLN1 gene. This alteration results from a G to T substitution at nucleotide position 1336, causing the valine (V) at amino acid position 446 to be replaced by a leucine (L). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1336G>T alteration was observed in 0.0016% (4/251458) of total alleles studied, with a frequency of 0.012% (4/34592) in the Latino subpopulation. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been observed homozygous in a patient with a severe presentation of mucolipidosis IV (Sun, 2000; Wakabayashi, 2011; Yamaguchi, 2019). Functional analysis reveals there may be a damaging effect of the amino acid alteration: _x000D_ _x000D_ Several studies have demonstrated using functional data that the p.V446L alteration can interfere with correct subcellular localization (Dong, 2008; Chen, 2014; Pryor, 2006). Other studies suggest the alteration impairs channel function (Dong, 2008), but this was not consistently observed (Raychowdhury, 2004). Based on the available evidence, this alteration is classified as likely pathogenic. |
| Labcorp Genetics |
RCV000194491 | SCV003443094 | uncertain significance | Mucolipidosis type IV | 2023-07-07 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 208033). 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: 14749347, 18794901, 25119295, 27670435). 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. This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11030752). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 446 of the MCOLN1 protein (p.Val446Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). |