ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.2665_2666delinsAT (p.Glu889Ile) (rs587778724)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468584 SCV000552353 uncertain significance Tuberous sclerosis 1 2018-05-25 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 21 of the TSC1 mRNA (c.2665_2666delGAinsAT), replacing glutamic acid with isoleucine at codon 889 of the TSC1 protein (p.Glu889Ile). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and isoleucine. This variant is reported as two separate single-nucleotide changes in the ExAC database (c.2665G>A and c.2666A>T), but the read data shows that the two variants are in cis, recapitulating the variant observed here (c.2665_2666delGAinsAT). However, the frequency data for this variant (rs587778724) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 135366). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000566373 SCV000675442 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
ITMI RCV000122193 SCV000086412 not provided not specified 2013-09-19 no assertion provided reference population

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