rs121918075
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000371.4(TTR):c.401A>G(p.Tyr134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y134H) has been classified as Pathogenic.
Frequency
Consequence
NM_000371.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.401A>G | p.Tyr134Cys | missense_variant | 4/4 | ENST00000237014.8 | |
LOC124904277 | XR_007066326.1 | n.129-2937T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.401A>G | p.Tyr134Cys | missense_variant | 4/4 | 1 | NM_000371.4 | P1 | |
TTR | ENST00000649620.1 | c.401A>G | p.Tyr134Cys | missense_variant | 6/6 | P1 | |||
TTR | ENST00000610404.5 | c.305A>G | p.Tyr102Cys | missense_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial amyloid neuropathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 21135536). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. ClinVar contains an entry for this variant (Variation ID: 13419). This variant is also known as Tyr114Cys or Y114C. This missense change has been observed in individuals with amyloidosis (PMID: 2161654, 21135536, 23713495). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the TTR protein (p.Tyr134Cys). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1992 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2020 | Published functional studies demonstrate that this variant has a damaging effect on the TTR protein (Zhang et al., 2011; Li et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The Y134C is also reported as Y114C in the published literature; This variant is associated with the following publications: (PMID: 26656838, 16217058, 21135536, 25382970, 31782077, 32353608, 31718691, 1330202, 27859927, 28943540, 2161654, 17503405, 15820680, 22620962, 23713495) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2023 | The c.401A>G (p.Y134C) alteration is located in exon 4 (coding exon 4) of the TTR gene. This alteration results from an A to G substitution at nucleotide position 401, causing the tyrosine (Y) at amino acid position 134 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referenced as p.Y114C) has been reported in the heterozygous state in multiple individuals with features consistent with adult-onset hereditary transthyretin-related amyloidosis and co-segregates with disease in several families (Du, 2021; Yamashita, 2019; Koike, 2018; Misumi, 2016; Ihse, 2013; Zhuang, 2022; Nakamura, 2005; Ueno, 1992; Ueno, 1990). Additionally, other missense variants at the same amino acid position, c.400T>C (p.Y134H) and c.401A>C (p.Y134S), have been described in individuals with features consistent with hereditary transthyretin-related amyloidosis (Matsushima, 2023; Nakase, 2019). This amino acid position is not well conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Wojtczak, 1996). In vitro functional studies indicate this alteration reduces TTR stability, alters oligomerization, and contributes to cytotoxicity (Sekijima, 2005; Zhang, 2011; Li, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at