NM_000371.4:c.233T>A

Variant names:

• chr18-31595152-T-A
• rs121918069
• NM_000371.4:c.233T>A
• TTR p.Leu78His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019): 18P and 0B. PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_000371.4(TTR):c.233T>A (p.Leu78His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000648564: Experimental studies have shown that this missense change affects TTR function (PMID:15820680, 19602727)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.L78V: Likely_pathogenic (ClinVar VariationId 1799566, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L78?: Uncertain_significance (ClinVar VariationId 2442894, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.06
• Publications: 21 publications found

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]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• carpal tunnel syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 18 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000648564: Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 19602727).; SCV002732384: 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).
• PM1: UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 146 pathogenic, 10 benign rare missense variants (OR vs. background: 69.8).; ±8 AA neighbourhood: 35 pathogenic, 0 benign (OR vs. background: 355.0).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.000888) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.L78V: Likely_pathogenic (ClinVar VariationId 1799566, 1 star); Other variants at the same amino acid residue (not pathogenic): p.L78?: Uncertain_significance (ClinVar VariationId 2442894, 2 stars)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000371.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.233T>A	p.Leu78His	missense	Exon 3 of 4	NP_000362.1	P02766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.233T>A	p.Leu78His	missense	Exon 3 of 4	ENSP00000237014.4	P02766
	TTR	ENST00000649620.1		c.233T>A	p.Leu78His	missense	Exon 5 of 6	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.233T>A	p.Leu78His	missense	Exon 5 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Amyloidosis, hereditary systemic 1 (4)
4	-	-	not provided (4)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.98
Mutation Taster		=16/84	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121918069;

hg19: chr18-29175115;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar