ClinVar Genomic variation as it relates to human health

ACMG classification criteria: PVS1, PS4, PM2, PM3

A heterozygous missense variation in exon 6 of the SMPD1 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variant c.1624C>T (p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as likely pathogenic.

A homozygous variation in exon 6 of the SMPD1 gene that results in a premature truncation of the protein at codon 542 was detected. The observed variant c.1624C>T(p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in gnomAD database. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33083013, 32860008, 27338287, 31139477, 22796693, 23188845, 33675270, 35534800)

The observed missense c.1163A>G (p.Lys388Arg) variant in STK11 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Lys388Arg variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submissions). Computational evidence (Polyphen - Possibly Damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Lys388Arg in STK11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Lys at position 388 is changed to a Arg 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).

Variant summary: SMPD1 c.1624C>T (p.Arg542X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251346 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A (0.00049 vs 0.0022). c.1624C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type A (Ranganath_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Arg542Ter variant in SMPD1 (also known as p.Arg540Ter due to a difference in cDNA numbering) has been reported in at least 14 individuals with Niemann-Pick disease (PMID: 22796693, 31139477, 27338287) and has been identified in 0.049% (15/30616) of South Asian chromosomes and 0.002% (1/113642) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123478). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported on ClinVar (VariationID: 93318) as Pathogenic by EGL Genetic Diagnostics and Invitae. This nonsense variant leads to a premature termination codon at position 542. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without the C-terminus region, which is critical to protein function (PMID: 21098024, 18052040). Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in at least 11 affected homozygotes and in combination with reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg542Ter variant is pathogenic (PMID: 22796693, 31139477, 27338287). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being less than 10% of normal, consistent with disease (PMID: 27338287, 22796693). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in the homozygous state and with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PP4, PM2_supporting (Richards 2015).

This sequence change creates a premature translational stop signal (p.Arg542*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the SMPD1 protein. This variant is present in population databases (rs398123478, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 22796693, 23188845, 27338287; Invitae). 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: 93318). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.