rs776749939

Variant names:

• chr5-179833777-C-T
• rs776749939
• NM_003900.5:c.1160C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_003900.5(SQSTM1):​c.1160C>T​(p.Pro387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.30
• Publications: 23 publications found

Genes affected

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003900.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 5-179833777-C-T is Pathogenic according to our data. Variant chr5-179833777-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202211.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1160C>T	p.Pro387Leu	missense_variant	Exon 7 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.908C>T	p.Pro303Leu	missense_variant	Exon 8 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.908C>T	p.Pro303Leu	missense_variant	Exon 8 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1160C>T	p.Pro387Leu	missense_variant	Exon 7 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.908C>T	p.Pro303Leu	missense_variant	Exon 6 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.950+550C>T		intron_variant	Intron 6 of 6	5		ENSP00000424477.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251090 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461822 Hom.: 1 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 727212

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53358

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112008

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000722 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SQSTM1-related disorder Pathogenic:1

Jun 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SQSTM1 c.1160C>T variant is predicted to result in the amino acid substitution p.Pro387Leu. This variant has been observed in several individuals with Paget’s disease or frontotemporal dementia (Le Ber et al 2013. PubMed ID: 24042580; Donáth et al 2020. PubMed ID: 32978683; Gennari et al 2010. PubMed ID: 20200946). In one study the c.1160C>T variant segregated with disease including three affected individuals with frontotemporal dementia having the variant and two unaffected individuals lacking the variant (van der Zee et al 2014. PubMed ID: 24899140). This variant has also been reported in a family with one individual with Paget's disease and in two unaffected individuals with highly elevated prediagnostic levels of serum alkaline phosphatase (Johnson-Pais et al 2003. PubMed ID: 14584883; Leach et al 2006. PubMed ID: 17229008). This variant has been reported to affect SQSTM1 protein function (Cavey et al. 2006. PubMed ID: 16691492). This variant is reported in 0.028% of alleles in individuals of European (Finnish) descent in gnomAD. However, the majority of individuals carrying the variant in gnomAD are below typical ages of disease on set and it is unclear if they would be affected. Together we classify this variant as likely pathogenic. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Pathogenic:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 11, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P387L variant in the SQSTM1 gene has been reported in individuals with Paget disease of bone as well as inindividuals with frontotemporal dementia (Johnson-Pais et al., 2003; Gennari et al., 2010; Le Ber et al., 2013; vander Zee et al., 2014). In vitro studies demonstrate that the P387L results in decreased binding of monoubiquitin andpolyubiquitin as compared to wild-type (Cavey et al., 2006). The P387L variant was not observed in approximately6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating itis not a common benign variant in these populations. The P387L variant is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties and occurs at aposition that is conserved across species. The P387L variant is a strong candidate for a pathogenic variant, howeverthe possibility it may be a rare benign variant cannot be excluded. -

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Uncertain:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 387 of the SQSTM1 protein (p.Pro387Leu). This variant is present in population databases (rs776749939, gnomAD 0.03%). This missense change has been observed in individual(s) with Paget disease, frontotemporal dementia or dementia (PMID: 14584883, 20200946, 22972638, 24042580, 24899140, 25796131, 29525180). ClinVar contains an entry for this variant (Variation ID: 202211). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SQSTM1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 16691492, 17229008). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.87	P;.
Vest4		0.77
MVP		0.99
MPC		0.26
ClinPred		0.25	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.61
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs776749939; hg19: chr5-179260777; COSMIC: COSV52972588; COSMIC: COSV52972588;