ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1660G>A (p.Ala554Thr)

gnomAD frequency: 0.00001  dbSNP: rs758811926
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001102622 SCV001259307 uncertain significance Niemann-Pick disease, type A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001239610 SCV001412494 uncertain significance Niemann-Pick disease, type B; Niemann-Pick disease, type A 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 554 of the SMPD1 protein (p.Ala554Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs758811926, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. 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 threonine 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.
Natera, Inc. RCV001102622 SCV002092292 uncertain significance Niemann-Pick disease, type A 2020-08-31 no assertion criteria provided clinical testing

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