ClinVar Genomic variation as it relates to human health

A homozygous missense variation in exon 5 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at codon 151 was detected. The observed variant c.452C>T(p.Pro151Leu) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. The allele frequency of the variant is Æ’ = 0.0000279 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic.

In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000873056, PMID:7633425, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000321205, PMID:7795586,23227063,27243974, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3CNET: 0.993, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro151 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22327063). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 151 of the GALNS protein (p.Pro151Leu). This variant is present in population databases (rs559063128, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 7633425, 8651279, 23876334). ClinVar contains an entry for this variant (Variation ID: 873056). 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) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function.

The observed missense c.6638G>A(p.Ser2213Asn) variant in MYO7A gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Ser2213Asn variant has been reported with allele frequency of 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidences (Polyphen - Benign, SIFT - Damaging and MutationTaster - Polymorphism) predict conflicting evidence on protein structure and function for this variant. The reference amino acid change at this position on MYO7A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2213 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).