Submissions for variant NM_000543.5(SMPD1):c.955G>C (p.Gly319Arg)

dbSNP: rs757934797

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671268	SCV000796225	uncertain significance	Niemann-Pick disease, type A	2017-12-05	criteria provided, single submitter	clinical testing
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV001527420	SCV001738420	likely pathogenic	Niemann-Pick disease, type B	2021-04-25	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV000671268	SCV002073032	likely pathogenic	Niemann-Pick disease, type A		criteria provided, single submitter	clinical testing	The missense variant p.G319R in SMPD1 (NM_000543.5) has been previously reported in homozygous state in an affected patient of Indian origin (Ranganath P et al, 2016). The variant has been submitted to ClinVar as Uncertain significance. The p.G319R variant is observed in 1/1,13,740 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G319R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 319 of SMPD1 is conserved in all mammalian species. The nucleotide c.955 in SMPD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
3billion	RCV001527420	SCV002572578	likely pathogenic	Niemann-Pick disease, type B	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMPD1-related disorder (ClinVar ID: VCV000555444 / PMID: 27338287). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27338287). A different missense change at the same codon (p.Gly319Ser) has been reported to be associated with SMPD1-related disorder (ClinVar ID: VCV000992693). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000671268	SCV004203239	likely pathogenic	Niemann-Pick disease, type A	2023-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767992	SCV004570145	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-05-20	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects SMPD1 function (PMID: 34273913). For these reasons, this variant has been classified as Pathogenic. 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 SMPD1 protein function. ClinVar contains an entry for this variant (Variation ID: 555444). This missense change has been observed in individual(s) with Niemann-Pick disease type A (PMID: 27338287). This variant is present in population databases (rs757934797, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 319 of the SMPD1 protein (p.Gly319Arg).