Submissions for variant NM_000371.4(TTR):c.200G>A (p.Gly67Glu)

dbSNP: rs121918090

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000990082	SCV001140870	pathogenic	Amyloidosis, hereditary systemic 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000990082	SCV001219052	pathogenic	Amyloidosis, hereditary systemic 1	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 67 of the TTR protein (p.Gly67Glu). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 12000196, 20209591; internal data). This variant is also known as p.Gly47Glu. ClinVar contains an entry for this variant (Variation ID: 803481). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts the c.200G nucleotide in the TTR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 26986100). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002416270	SCV002722872	pathogenic	Cardiovascular phenotype	2014-09-24	criteria provided, single submitter	clinical testing	The p.G67E pathogenic mutation (also known as c.200G>A and G47E), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 200. The amino acid change results in glycine to glutamic acid at codon 67. This change occurs in the last base pair of exon 2 which makes it likely to have some effect on normal mRNA splicing; however, direct evidence is not available. Two disease-causing mutations, p.G67A and p.G67R, have been described in the same codon. This pathogenic mutation was first identified in two siblings presenting in their late third decade with peripheral neuropathy, autonomic dysfunction and a family history consistent with familial amyloid polyneuropathy; there was rapid progression of disease in this family along with anticipation in the age of onset of symptoms (Pelo E et al. Amyloid. 2002;9(1):35-41). A functional study found this mutation lead to decreased conformational stability (Altland K et al. Electrophoresis. 2007;28(12):2053-64). An additional study identified this mutation in two unrelated individuals presenting with predominantly neurologic symptoms in their fourth decade; both patients had symptoms of renal impairment, motoric, sensoric, and autonomic polyneuropathy and one patient additionally had restrictive cardiac function (Barreiros AP et al. Liver Transpl. 2010;16(3):314-23). Based on the supporting evidence, p.G67E is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000990082	SCV005727149	pathogenic	Amyloidosis, hereditary systemic 1	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: TTR c.200G>A (p.Gly67Glu) results in a non-conservative amino acid change located in the Transthyretin domain (IPR023416) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251660 control chromosomes. c.200G>A has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (e.g. Pelo_2002, Haagsma_2004, Lachmann_2002, Rapezzi_2013, Labcorp (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. Multiple different variants located at the same codon (p.Gly67Ala, p.Gly67Val) have been classified as pathogenic by our lab supporting a critical relevance of this residue to TTR protein function. The following publications have been ascertained in the context of this evaluation (PMID: 22745357, 15185498, 12050338, 12000196). ClinVar contains an entry for this variant (Variation ID: 803481). Based on the evidence outlined above, the variant was classified as pathogenic.