rs794727780

chr11-6394536-TGCC-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_000543.5(SMPD1):c.1829_1831del(p.Arg610del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,609,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 8.39

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000543.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-6394536-TGCC-T is Pathogenic according to our data. Variant chr11-6394536-TGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 198093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394536-TGCC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1829_1831del	p.Arg610del	inframe_deletion	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1829_1831del	p.Arg610del	inframe_deletion	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000218 AC: 54 AN: 247548 Hom.: 0 AF XY: 0.000201 AC XY: 27 AN XY: 134314

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000545

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1457516 Hom.: 0 AF XY: 0.000171 AC XY: 124 AN XY: 725332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000407

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000196

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type B Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.022%). Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. 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: 1885770). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000198093 / PMID: 1885770). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	Found on almost 90% of disease alleles in individuals with non-neuronopathic acid sphingomyelinase defciency (Niemann-Pick disease, type B [NPD]) from North Africa (Maghred region: Tunisia, Algeria, and Morocco), in almost all patients with type B NPD from the Gran Canaria Island, and also on approximately 20%-30% of disease alleles in individuals with type B NPD from the United States (Fernandez-Burriel et al. 2003; Wasserstein and Schuchman, 2015); Expression studies found that c.1829_1831delGCC is associated with approximately 21% of wild-type sphingomyelin phosphodiesterase 1 enzyme activity consistent with the less severe type B phenotype (Rodrguez-Pascau et al. 2009); In-frame deletion of one amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 1885770, 18815062, 21502868, 8225311, 19405096, 21228398, 12694237, 30223864, 30153451, 29626972, 27884455, 28492532, 15545621, 11932991, 8401540, 21098024, 30795770, 29948344, 31122880, 30870388, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -

Niemann-Pick disease, type A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_000543.4(SMPD1):c.1829_1831delGCC(R610del, aka deltaR608) is classified as pathogenic in the context of SMPD1-related Niemann-Pick disease. Sources cited for classification include the following: PMID 21502868, 19405096 and 8225311. Classification of NM_000543.4(SMPD1):c.1829_1831delGCC(R610del, aka deltaR608) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Sphingomyelin/cholesterol lipidosis Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Homozygotes have milder clinical course. One of the most common pathogenic variants in persons with Niemann-Pick disease type-B. In persons with Niemann-Pick disease type-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles. On Gran Canaria Island, accounts for 100% of pathogenic alleles. Accounts for approximately 20%-30% of pathogenic variants in those with Niemann-Pick disease type-B in the US. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 04, 2019

Variant summary: SMPD1 c.1829_1831delGCC (p.Arg610del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00021 in 242558 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick disease type B (0.00021 vs 0.0022). c.1829_1831delGCC has been reported in the literature as a common disease variant in several homozygous and compound heterozygous individuals affected with Niemann-Pick disease type B (e.g. Vanier 1993, Simonaro 2002, Rodriguez-Pascau 2009, Zampieri 2015). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced enzyme activity (Vanier 1993, Rodriguez-Pascau 2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

SMPD1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

The SMPD1 c.1829_1831delGCC variant is predicted to result in an in-frame deletion (p.Arg610del). This variant, also known as p.Arg608del, has been reported in numerous individuals with Niemann-Pick disease, type B (Levran et al. 1991. PubMed ID: 1885770; Irun et al. 2013. PubMed ID: 23252888; Lipiński et al. 2019. PubMed ID: 30795770). Functional studies showed that the p.Arg610del variant could lead to a reduced sphingomyelinase activity (Rodríguez-Pascau et al. 2009. PubMed ID: 19405096). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This variant, c.1829_1831del, results in the deletion of 1 amino acid(s) of the SMPD1 protein (p.Arg610del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769777506, gnomAD 0.04%). This variant has been observed in individuals with Niemann-Pick type B (PMID: 1885770, 8225311, 12694237, 19405096, 23252888, 24643943). It has also been observed to segregate with disease in related individuals. This variant is also known as DR608. ClinVar contains an entry for this variant (Variation ID: 198093). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SMPD1 function (PMID: 18815062, 19405096). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs120074118; hg19: chr11-6415766;