rs121918073

chr18-31598622-C-Achr18-31598622-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000371.4(TTR):c.391C>A(p.Leu131Met) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L131L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.61

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 18-31598622-C-A is Pathogenic according to our data. Variant chr18-31598622-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13424.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-31598622-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.391C>A	p.Leu131Met	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2927G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.391C>A	p.Leu131Met	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.391C>A	p.Leu131Met	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.295C>A	p.Leu99Met	missense_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2023

The p.L131M variant (also known as c.391C>A), located in coding exon 4 of the TTR gene, results from a C to A substitution at nucleotide position 391. The leucine at codon 131 is replaced by methionine, an amino acid with highly similar properties. This alteration, which is also reported as p.L111M, has been detected in several individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy and TTR amyloidosis cohorts (Nordlie M et al. Scand J Immunol, 1988 Jan;27:119-22; Altland K et al. Electrophoresis, 2007 Jun;28:2053-64; Nelson LM et al. Clin Transplant, 2013 Dec;27:203-9; Suhr OB et al. Transplantation, 2016 Feb;100:373-81; Damy T et al. Eur Heart J, 2019 Apr;43:391-400; Caponetti AG et al. JACC Heart Fail, 2021 Oct;9:736-746; Barroso FA et al. Amyloid, 2022 Sep;29:175-183; Dispenzieri A et al. Orphanet J Rare Dis, 2022 Jun;17:236). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial amyloid neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
Polyphen		1.0	D;D;.
Vest4		0.66, 0.83
MutPred		0.88		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
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: rs121918073; hg19: chr18-29178585;