rs121918094

Positions:

• chr18-31592921-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.95T>C​(p.Leu32Pro) 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 (★★).

• 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: 6.11

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 16 ACMG points.

• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 18-31592921-T-C is Pathogenic according to our data. Variant chr18-31592921-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592921-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.95T>C	p.Leu32Pro	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.95T>C	p.Leu32Pro	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:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 23, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). 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: 13457). This variant is also known as Leu12Pro. This missense change has been observed in individual(s) with TTR-related conditions (PMID: 10071047, 20209591). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 32 of the TTR protein (p.Leu32Pro). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 05, 2019

The TTR c.95T>C; p.Leu32Pro variant (rs121918094), also known as p.Leu12Pro in alternative nomenclature, is reported in the literature in multiple individuals affected with TTR amyloidosis, including several individuals presenting with leptomeningeal amyloidosis (Brett 1999, McColgan 2015) and two siblings presenting with seizures and hypertrophic heart disease (Barreiros 2010). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 32 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, functional studies indicate that variant protein forms aggregates in cultured cells and mouse hepatocytes (Batista 2013) and exhibits altered multimerization properties compared to wildtype protein (Altland 2007). Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Barreiros AP et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl. 2010 Mar;16(3):314-23. Batista AR et al. Hepatic production of transthyretin L12P leads to intracellular lysosomal aggregates in a new somatic transgenic mouse model. Biochim Biophys Acta. 2013 Aug;1832(8):1183-93. Brett M et al. Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain. 1999 Feb;122 ( Pt 2):183-90. McColgan P et al. Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient. J Neurol. 2015 Jan;262(1):228-34. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.1	.;D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96, 0.96, 0.93
MutPred		0.93		Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		1.0

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: rs121918094; hg19: chr18-29172884;