Submissions for variant NM_000371.4(TTR):c.200G>T (p.Gly67Val)

dbSNP: rs121918090

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001207386	SCV001378733	likely pathogenic	Familial amyloid neuropathy	2019-06-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly67 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20209591, 12000196). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 25997029, 26986100). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 67 of the TTR protein (p.Gly67Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 2 of the TTR coding sequence, which is part of the consensus splice site for this exon.
Ambry Genetics	RCV002418694	SCV002722875	pathogenic	Cardiovascular phenotype	2019-04-03	criteria provided, single submitter	clinical testing	The c.200G>T pathogenic mutation (also known as p.G67V), located in coding exon 2 of the TTR gene, results from a G to T substitution at nucleotide position 200. The amino acid change results in glycine to valine at codon 67, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in multiple individuals with TTR-related amyloidosis (Saraiva MJ. Hum. Mutat., 1995;5:191-6; Suenaga G et al. Sci Rep, 2017 05;7:1579). Different alterations at this same position (c.200G>C G67A, c.200G>A G67E) have been reported in multiple individuals with TTR-related amyloidosis (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Pelo E et al. Amyloid, 2002 Mar;9:35-41; Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001207386	SCV004813562	pathogenic	Familial amyloid neuropathy	2024-02-13	criteria provided, single submitter	clinical testing	Variant summary: TTR c.200G>T (p.Gly67Val) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase 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 251460 control chromosomes (gnomAD). c.200G>T has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (Gillmore_2015, Gillmore_2016, Low_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26243339, 27143678, 34059423). ClinVar contains an entry for this variant (Variation ID: 938206). Based on the evidence outlined above, the variant was classified as pathogenic.