rs121918069

chr18-31595152-T-Achr18-31595152-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.233T>A(p.Leu78His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L78R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.06

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 hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr18-31595152-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13435.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 18-31595152-T-A is Pathogenic according to our data. Variant chr18-31595152-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595152-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.233T>A	p.Leu78His	missense_variant	3/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.233T>A	p.Leu78His	missense_variant	3/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.233T>A	p.Leu78His	missense_variant	5/6			P1
TTR	ENST00000610404.5	c.137T>A	p.Leu46His	missense_variant	3/4	5
TTR	ENST00000541025.2	n.259T>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2016	Variant summary: The TTR c.233T>A (p.Leu78His) variant indicated to be located in the loop region (Cendron_2009) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. In addition, mutations in this residue (L78R) and in nearby residues (H76R, G77R, T79R, T79K) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and is a common TTR disease variant that is reported to be detected in >50 published cases, usually presenting with carpal tunnel syndrome and slowly progressing over two decades (Miller_2004). Multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the TTR protein (p.Leu78His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2613237, 9196903, 17503405, 20209591, 25526974, 27724962). This variant is also known as p.Leu58His. ClinVar contains an entry for this variant (Variation ID: 13420). 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%. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 19602727). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 27, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 31, 2022	_x000D_ Criteria applied: PS3, PM2_SUP, PM1_SUP, PM5, PS4_MOD -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2023	Identified in association with amyloidosis and amyloidotic polyneuropathy (Nichols et al., 1989; Barreiros et al., 2010; Suhr et al., 2016; Tebbe et al., 2016; Skrahina et al., 2021; Trachtenberg et al., 2021; Ungerer et al., 2021); also reported as L58H due to alternative nomenclature; Functional studies have shown that L78H, located in the loop region, results in a small but significant conformational change that affects the stability of the protein tetramer (Sekijima et al., 2005; Atland et al., 2007; Cendron et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 1644839, 17503405, 19602727, 22620962, 25526974, 2613237, 27724962, 17143887, 1656975, 25604431, 26656838, 20209591, 15820680, 34461735, 34658264, 33283548, 37014422) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2016	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2021

The p.L78H variant (also known as c.233T>A and L58H), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 233. The leucine at codon 78 is replaced by histidine, an amino acid with similar properties. This alteration has been seen in multiple individuals with familial transthyretin amyloidosis whose symptoms generally included carpal tunnel syndrome, generalized neuropathy, amyloid deposits and positive congo red staining (Nichols WC, et al. Genomics 1989;5(3):535-40; Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Connors LH, et al. Biochim. Biophys. Acta 1998;1407(3):185-92; Ungerer MN et al. Amyloid, 2020 Dec;:1-9). In two additional studies, a small difference in the crystal structure of this variant compared with wild type was noted and the variant was shown to unfold 90% at 2.5M urea, indicating decreased conformation stability in the folded state (Altland K, et al. Electrophoresis 2007;28(12):2053-64; Cendron L, et al. J. Biol. Chem. 2009 Sep; 284(38):25832-41). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zhang J et al. Environ Sci Technol, 2018 10;52:11865-11874). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;D;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
Polyphen		1.0	D;D;.;.
Vest4		0.92, 0.91, 0.95
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
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: rs121918069; hg19: chr18-29175115;