Submissions for variant NM_020533.3(MCOLN1):c.452G>A (p.Arg151His)

dbSNP: rs140148914

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002547622	SCV003508274	uncertain significance	Mucolipidosis type IV	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 151 of the MCOLN1 protein (p.Arg151His). This variant is present in population databases (rs140148914, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MCOLN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049590). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355906	SCV001550924	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MCOLN1 p.Arg151His variant was not identified in the literature nor was it identified in the ClinVar or Cosmic databases. The variant was identified in dbSNP (ID: rs140148914), MutDB and LOVD 3.0. The variant was identified in control databases in 10 of 246228 chromosomes at a frequency of 0.000041 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 3 of 30782 chromosomes (freq: 0.000097), European (Non-Finnish) in 6 of 111684 chromosomes (freq: 0.000054) and European (Finnish) in 1 of 22294 chromosomes (freq: 0.000045); it was not observed in the African, Ashkenazi Jewish, East Asian, Latino and other populations. The p.Arg151His residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.