rs79977247

Positions:

• chr18-31592975-T-C
• chr18-31592975-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.149T>C​(p.Val50Ala) variant causes a missense change. 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. V50G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.48

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 6) in uniprot entity TTHY_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31592975-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 18-31592975-T-C is Pathogenic according to our data. Variant chr18-31592975-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592975-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.149T>C	p.Val50Ala	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.149T>C	p.Val50Ala	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: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2019	Variant summary: TTR c.149T>C (p.Val50Ala) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). c.149T>C has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (e.g. Liu_2017, Meng_2015, Nepomuceno_2004, Suhr_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggest that the variant promotes the formation of unfolded monomers and amyloid fibrils, which potentially contribute to increased neurotoxicity and pathology (Zhang_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 18, 2021	This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22620962, 22745357, 23833285, 24455802, 24555660, 26115788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TTR protein function (PMID: 23523753). 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: 13430). This variant is also known as Val30Ala. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1544214, 12757474, 17503405, 22745357, 26521788). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 50 of the TTR protein (p.Val50Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.95	D;D;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	.;D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	.;D;.;.
Sift4G	Benign	0.14	.;T;T;D
Polyphen		0.43	B;B;.;.
Vest4		0.65, 0.75, 0.82
MutPred		0.82		Loss of stability (P = 0.0351);Loss of stability (P = 0.0351);Loss of stability (P = 0.0351);Loss of stability (P = 0.0351);
MVP		0.98
MPC		0.87
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.98

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: rs79977247; hg19: chr18-29172938;