rs876658108

chr18-31598649-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000371.4(TTR):c.418G>T(p.Ala140Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A140A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.68

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 18-31598649-G-T is Pathogenic according to our data. Variant chr18-31598649-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229597.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}. Variant chr18-31598649-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.418G>T	p.Ala140Ser	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2954C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.418G>T	p.Ala140Ser	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.418G>T	p.Ala140Ser	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.322G>T	p.Ala108Ser	missense_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The p.A140S variant (also known as c.418G>T and p.A120S), located in coding exon 4 of the TTR gene, results from a G to T substitution at nucleotide position 418. The alanine at codon 140 is replaced by serine, an amino acid with similar properties. This variant, which is also known as p.A120S, has been reported in multiple individuals with transthyretin (TTR) amyloidosis (Gürsoy AE et al. Neurol India;66:238-241; Patel K et al. Amyloid, 2018 09;25:211-212; Iorio A et al. Eur J Hum Genet, 2017 09;25:1055-1060; Shibata Y et al. Amyloid, 2017 03;24:66-67; Luigetti M et al. Neurol Sci, 2013 Jul;34:1057-63; Lachmann HJ et al. N Engl J Med, 2002 Jun;346:1786-91; Adams D et al. Neurology, 2015 Aug;85:675-82). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial amyloid neuropathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 140 of the TTR protein (p.Ala140Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial transthyretin amyloidosis (PMID: 12050338, 22592564, 26208957, 28635949). This variant is also known as p.Ala120Ser. ClinVar contains an entry for this variant (Variation ID: 229597). 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.Ala140 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 12050338, 22209138, 26208957, 28635949), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 17, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala140Ser (also reported as p.Ala120Ser) variant in TTR has been reported in 2 individual s with clinical features of familial transthyretin amyloidosis (Lachmann 2002, C onnors 2003, Luigetti 2013) and was absent from large population studies. Comput ational prediction tools and conservation analysis suggest that the p.Ala140Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pat hogenic role, the clinical significance of the clinical significance of the p.Al a140Ser variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 23, 2017

Variant summary: The TTR c.418G>T (p.Ala140Ser) variant located in the beta strand 11 (via Polimanti_2014) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 121370 control chromosomes (ExAC). Multiple publications have cited the variant, however, due to geographical/site overlap, it seems as though the same two affected patients are being cited, therefore, there is limited available clinical studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Until functional data and additional clinical data become available, this variant is classified as a "Variant of Uncertain Significance - Possibly Pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
Polyphen		0.99	D;D;.;.
Vest4		0.61, 0.67, 0.87
MutPred		0.81		Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);.;.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876658108; hg19: chr18-29178612;