ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.605G>A (p.Arg202His)

gnomAD frequency: 0.00004  dbSNP: rs757850587
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS RCV001527415 SCV001738414 pathogenic Niemann-Pick disease, type A 2021-04-25 criteria provided, single submitter research
GeneDx RCV002469402 SCV002765897 uncertain significance not provided 2022-12-13 criteria provided, single submitter clinical testing Observed in the apparent homozygous state in a patient in the literature with hepatomegaly, but no other clinical information was available on this patient (Deshpande et al., 2021); Published functional studies demonstrate a damaging effect: significantly reduced enzyme activity (Deshpande et al., 2021); This variant is associated with the following publications: (PMID: 34273913)
Invitae RCV002568141 SCV003466193 uncertain significance Niemann-Pick disease, type B; Niemann-Pick disease, type A 2022-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 202 of the SMPD1 protein (p.Arg202His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of acid sphingomyelinase deficiency (PMID: 34273913). ClinVar contains an entry for this variant (Variation ID: 1173966). 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. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 34273913). 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.
Ambry Genetics RCV004039188 SCV004954304 uncertain significance Inborn genetic diseases 2021-08-23 criteria provided, single submitter clinical testing The c.605G>A (p.R202H) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution at nucleotide position 605, causing the arginine (R) at amino acid position 202 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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