rs730881165
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP4
The NM_000371.4(TTR):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000371.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.301G>A | p.Ala101Thr | missense_variant | 3/4 | ENST00000237014.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.301G>A | p.Ala101Thr | missense_variant | 3/4 | 1 | NM_000371.4 | P1 | |
TTR | ENST00000649620.1 | c.301G>A | p.Ala101Thr | missense_variant | 5/6 | P1 | |||
TTR | ENST00000610404.5 | c.205G>A | p.Ala69Thr | missense_variant | 3/4 | 5 | |||
TTR | ENST00000541025.2 | n.327G>A | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251436Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727236
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 26, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 04, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2023 | Variant summary: TTR c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change located in the transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251436 control chromosomes (gnomAD). c.301G>A has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis, however often with limited evidence for causality (i.e. lack of segregation data or family history) (e.g. Benson_2003, Connors_2003, Obici_2012, Quarta_2014, Sperry_2018, Damy_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further information becomes available. - |
Familial amyloid neuropathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 101 of the TTR protein (p.Ala101Thr). This variant is present in population databases (rs730881165, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of TTR-related conditions (PMID: 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 181696). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala101 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 12, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2019 | Reported in a patient with a TTR-related cardiac phenotype in the published literature (Connors et al., 2003); reported as Ala81Thr due to the use of alternate nomenclature; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 181696; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17338921, 15123043, 22551192, 14640030, 15645642) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2023 | The p.A101T variant (also known as c.301G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 301. The alanine at codon 101 is replaced by threonine, an amino acid with similar properties. This variant has been reported several times in the literature in patients with some features of hereditary transthyretin (hATTR) amyloidosis; however, the diagnosis of hATTR amyloidosis was immunohistochemically-confirmed in only one proband (Benson MD et al. Muscle Nerve, 2007 Oct;36:411-23; Obici L et al. Amyloid, 2012 Jun;19 Suppl 1:34-6; Quarta CC et al. Circulation, 2014 May;129:1840-9; Sperry BW et al. J. Am. Coll. Cardiol., 2018 10;72:2040-2050). Based on internal structural assessment, this alteration leads to destabilization of the native form of TTR that is similar to other established pathogenic variants in the vicinity (Wojtczak A et al. Acta Crystallogr. D Biol. Crystallogr., 1996 Jul;52:758-65; Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at