rs118203640

Variant names:

• chr9-132903752-G-GTAAC
• rs118203638
• NM_000368.5:c.2103_2106dupGTTA

Your query was ambiguous. Multiple possible variants found:

• chr9-132903752-G-GTAAC
• chr9-132903752-GTAAC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000368.5(TSC1):​c.2103_2106dupGTTA​(p.Leu703ValfsTer4) variant causes a frameshift change involving the alteration of a non-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, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: -0.0980

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 18 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 9-132903752-G-GTAAC is Pathogenic according to our data. Variant chr9-132903752-G-GTAAC is described in ClinVar as [Pathogenic]. Clinvar id is 64707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2103_2106dupGTTA	p.Leu703ValfsTer4	frameshift_variant	Exon 17 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2103_2106dupGTTA	p.Leu703ValfsTer4	frameshift_variant	Exon 17 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2103_2106dupGTTA	p.Leu703ValfsTer4	frameshift_variant	Exon 18 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 07, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2103_2106dupGTTA pathogenic variant in the TSC1 gene has been reported previously in an individual with a clinical diagnosis of TSC (TSC1 LOVD). This pathogenic variant causes a frameshift starting with codon Leucine 703, changes this amino acid to a Valine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu703ValfsX4. Thec.2103_2106dupGTTA variant is predicted to cause loss of normal protein function either throughprotein truncation or nonsense-mediated mRNA decay. Additionally, it is not observed in large population cohorts (Lek et al., 2016). Furthermore, other frameshift variants downstream of this position in the TSC1 protein have been reported in the Human Gene Mutation Database in association with TSC (Stenson et al., 2014). Therefore, the c.2103_2106dupGTTA variant is considered a pathogenic variant and its presence is consistent with the diagnosis of TSC in this individual. -

Tuberous sclerosis 1 Pathogenic:1

Nov 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu703Valfs*4) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 21510812). ClinVar contains an entry for this variant (Variation ID: 64707). For these reasons, this variant has been classified as Pathogenic. -

Tuberous sclerosis syndrome Other:1

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Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203638; hg19: chr9-135779139;