7-151490962-GT-TA

Position:

• chr7-151490962-GT-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_005614.4(RHEB):​c.104_105delinsTA​(p.Tyr35Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y35N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHEB NM_005614.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.74

Genes affected

RHEB (HGNC:10011): (Ras homolog, mTORC1 binding) This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 6) in uniprot entity RHEB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005614.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-151490963-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 376516.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 7-151490962-GT-TA is Pathogenic according to our data. Variant chr7-151490962-GT-TA is described in ClinVar as [Pathogenic]. Clinvar id is 3238630.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHEB	NM_005614.4	c.104_105delinsTA	p.Tyr35Leu	missense_variant	2/8	ENST00000262187.10
RHEB	XM_011516457.3	c.71_72delinsTA	p.Tyr24Leu	missense_variant	3/9
RHEB	XM_024446854.2	c.71_72delinsTA	p.Tyr24Leu	missense_variant	3/9
RHEB	XM_047420685.1	c.71_72delinsTA	p.Tyr24Leu	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHEB	ENST00000262187.10	c.104_105delinsTA	p.Tyr35Leu	missense_variant	2/8	1	NM_005614.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated focal cortical dysplasia type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jan 09, 2024

The RHEB c.104_105delinsTA (p.Tyr35Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been observed as a somatic mutation in one individual with tuberous sclerosis complex and multiple individuals with focal cortical dysplasia and/or hemimegalencephaly (Lee WS et al., PMID: 37015817; Zhao S et al., PMID: 31337748; Baldassari S et al., PMID: 31444548; Lee WS et al., PMID: 33434304). Two other variants in the same codon, c.104A>C (p.Tyr35Ser) and c.104A>G (p.Tyr35Cys) are reported in ClinVar and both are considered pathogenic (ClinVar Variation IDs 1702651 and 376516). This variant is absent from the general population (gnomAD v.4.0.0), indicating it is not a common variant. Functional studies show that in utero electroporation of the RHEB c.104_105delinsTA (p.Tyr35Leu) variant in mice induced S6 phosphorylation, cytomegalic neurons, dysregulated neuron migration, abnormal electroencephalogram, and seizures and that rapamycin treatment rescued abnormal electroencephalogram and alleviated seizures in these mice (Zhao S et al., PMID: 31337748). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the RHEB c.104_105delinsTA (p.Tyr35Leu) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-151188048;