ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.1884_1887AAAG[1] (p.Lys630fs)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189868 SCV000243521 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing The c.1888_1891delAAAG pathogenic variant in the TSC1 gene has been reported multiple times previously in association with tuberous sclerosis complex (van Slegtenhorst et al., 1997; Jones et al., 1997). The c.1888_1891delAAAG variant was previously reported as 2105delAAAG due to use of alternative nomenclature (van Slegtenhorst et al., 1997; Jones et al., 1997). The deletion causes a frameshift starting with codon Lysine 630, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Lys630GlnfsX22. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, the c.1888_1891delAAAG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the presence of c.1888_1891delAAAG is consistent with a diagnosis of tuberous sclerosis complex.
Athena Diagnostics Inc RCV000005403 SCV000255852 pathogenic Tuberous sclerosis 1 2014-10-10 criteria provided, single submitter clinical testing
Invitae RCV000005403 SCV000552318 pathogenic Tuberous sclerosis 1 2019-11-18 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 15 of the TSC1 mRNA (c.1888_1891delAAAG), causing a frameshift at codon 630. This creates a premature translational stop signal (p.Lys630Glnfs*22) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic. This particular variant has been reported as a recurrent pathogenic variant in several sporadic and familial tuberous sclerosis cases (PMID: 9242607, 9328481, 9863590, 9924605, 10533067). This variant is also known as 2105delAAAG and 2109_2112delAAAG in the literature. ClinVar contains an entry for this variant (Variation ID: 5097). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000005403 SCV000782390 pathogenic Tuberous sclerosis 1 2016-11-01 criteria provided, single submitter clinical testing
OMIM RCV000005403 SCV000025585 pathogenic Tuberous sclerosis 1 1997-08-08 no assertion criteria provided literature only
Tuberous sclerosis database (TSC1) RCV000042099 SCV000065883 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC1) RCV000042099 SCV000083153 not provided Tuberous sclerosis syndrome no assertion provided curation
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University RCV000005403 SCV001370496 pathogenic Tuberous sclerosis 1 2020-06-09 no assertion criteria provided clinical testing

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