Submissions for variant NM_000371.4(TTR):c.69G>A (p.Thr23=)

gnomAD frequency: 0.00001  dbSNP: rs752579437

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000828910	SCV000970615	likely benign	not provided	2018-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002372375	SCV002668082	uncertain significance	Cardiovascular phenotype	2022-07-19	criteria provided, single submitter	clinical testing	The c.69G>A variant (also known as p.T23T), located in coding exon 1 of the TTR gene, results from a G to A substitution at nucleotide position 69. This nucleotide substitution does not change the threonine at codon 23. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469304	SCV002766021	uncertain significance	not specified	2022-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV002538272	SCV003265043	uncertain significance	Familial amyloid neuropathy	2022-07-15	criteria provided, single submitter	clinical testing	This sequence change affects codon 23 of the TTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TTR protein. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is present in population databases (rs752579437, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 669808). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.