rs11541796

Positions:

• chr18-31593011-A-C
• chr18-31593011-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000237014.8(TTR):​c.185A>C​(p.Glu62Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E62D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR ENST00000237014.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.26

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000237014.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31593012-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1068392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.185A>C	p.Glu62Ala	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.185A>C	p.Glu62Ala	missense_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Nov 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.81	D;D;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	.;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.4	M;M;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	.;N;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.14	.;T;.;.
Sift4G	Benign	0.32	.;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.24, 0.29, 0.36
MutPred		0.50		Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);
MVP		0.99
MPC		0.54
ClinPred		0.63	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-29172974;