Submissions for variant NM_000543.5(SMPD1):c.56del (p.Gln19fs)

dbSNP: rs1554933746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674668	SCV000800047	likely pathogenic	Niemann-Pick disease, type A	2018-05-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674668	SCV000914523	uncertain significance	Niemann-Pick disease, type A	2017-07-11	criteria provided, single submitter	clinical testing	The SMPD1 c.56delA (p.Gln19ArgfsTer58) variant results in a frameshift, and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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 and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for SMPD1-related disorders.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003768012	SCV004588101	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln19Argfs*58) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 558404). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000674668	SCV005086073	pathogenic	Niemann-Pick disease, type A	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Niemann-Pick disease, type B, (MIM#607616), and Niemann-Pick disease, type A, (MIM#257200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once as likely pathogenic, and once as a VUS as part of a screening study (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV003768012	SCV005684489	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-05-23	criteria provided, single submitter	clinical testing