rs118203712

Positions:

• chr9-132900770-TC-T
• chr9-132900770-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000368.5(TSC1):​c.2569del​(p.Glu857ArgfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.65

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-132900770-TC-T is Pathogenic according to our data. Variant chr9-132900770-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 48977.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic]. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic]. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2569del	p.Glu857ArgfsTer21	frameshift_variant	20/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2569del	p.Glu857ArgfsTer21	frameshift_variant	20/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2014

c.2569delG: p.Glu857ArgfsX21 (E857RfsX21) in exon 20 of the TSC1 gene (NM_000368.4). The normal sequence with the base that is deleted in braces is: TGGG{G}AGGT. The c.2569delG mutation in the TSC1 gene has been reported previously in association with TSC (van Slegtenhorst et al., 1999; Sancak et al., 2005). The deletion causes a frameshift starting with codon Glutamic acid 857, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Glu857ArgfsX21. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Other frameshift mutations, including one caused by a duplication at the same position (c.2569dupG), have been reported in association with TSC (Dabora et al., 2001). This result is consistent with a diagnosis of tuberous sclerosis complex. The variant is found in INFANT-EPI panel(s). -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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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: rs118203712; hg19: chr9-135776157;