ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Reported previously in published literature in an individual submitted for NGS panel testing for congenital disorders of glycosylation; no additional phenotypic or familial segregation details were provided (Jones et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in 273/277240 (0.099%) alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23806237)

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 245 of the MGAT2 protein (p.Val245Leu). This variant is present in population databases (rs117536357, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of a congenital disorder of glycosylation (PMID: 23806237). ClinVar contains an entry for this variant (Variation ID: 94062). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

Converted during submission to Uncertain significance.

The MGAT2 p.Val245Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs117536357), ClinVar (classified as a VUS by EGL Genetics Diagnostics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital) and LOVD 3.0. The variant was also identified in control databases in 284 of 282872 chromosomes (1 homozygous) at a frequency of 0.001004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 16 of 7224 chromosomes (freq: 0.002215), European (non-Finnish) in 226 of 129192 chromosomes (freq: 0.001749), Ashkenazi Jewish in 15 of 10370 chromosomes (freq: 0.001446), European (Finnish) in 11 of 25116 chromosomes (freq: 0.000438), Latino in 12 of 35440 chromosomes (freq: 0.000339), African in 3 of 24960 chromosomes (freq: 0.00012) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val245 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.