18-31592983-T-C

Variant names:

• chr18-31592983-T-C
• rs121918068
• NM_000371.4:c.157T>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.157T>C​(p.Phe53Leu) 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. F53I) 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:6
• Conservation: PhyloP100: 4.45
• Publications: 24 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 Submitted by: G2P
• familial amyloid neuropathy

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr18-31592983-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13418.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 18-31592983-T-C is Pathogenic according to our data. Variant chr18-31592983-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.157T>C	p.Phe53Leu	missense_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.157T>C	p.Phe53Leu	missense_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 20, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple individuals with transthyretin-related amyloidosis and/or amyloid cardiomyopathy. In some published literature, this variant is referred to as Phe33Leu. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict this variant is damaging. -

Feb 13, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTR c.157T>C; p.Phe53Leu variant (rs121918068), also known as Phe33Leu, is reported in the literature in multiple individuals affected with TTR amyloidosis or amyloid polyneuropathy (Altland 2007, Barreiros 2010, Chen 2014, Connors 2003, Ihse 2013, Ii 1991). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The phenylalanine at codon 53 is moderately conserved, and functional studies show altered multimerization properties (Altland 2007). Additionally, other amino acid substitutions at this codon (Cys, Ile, and Val) have been reported in individuals with TTR amyloidosis and are considered disease-causing (Altland 2007, Connors 2003, Venkatesh 2017). Based on available information, the p.Phe53Leu 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. Chen CH et al. A case of familial amyloidotic polyneuropathy with a rare Phe33Leu mutation in the TTR gene. J Formos Med Assoc. 2014 Aug;113(8):575-6. Connors LH et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. Ii S et al. Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology. 1991 Jun;41(6):893-8. Venkatesh P et al. Vitreous Amyloidosis: Ocular, Systemic, and Genetic Insights. Ophthalmology. 2017 Jul;124(7):1014-1022. -

Jan 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Published functional studies demonstrate a damaging effect; the variant destabilizes TTR monomers (Altland et al., 2007); This variant is associated with the following publications: (PMID: 9798666, 26521788, 31932463, 1932142, 20209591, 2046936, 33373035, 32789836, 34440326, 33739616, 23713495, 17503405) -

Amyloidosis, hereditary systemic 1 Pathogenic:2

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 53 of the TTR protein (p.Phe53Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated (hATTR) amyloidosis (PMID: 1932142, 2046936, 9798666, 17503405, 20209591, 23713495). This variant is also known as Phe33Leu (F33L). ClinVar contains an entry for this variant (Variation ID: 13456). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. This variant disrupts the p.Phe53 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15478468, 17503405, 20558946, 22745357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Jan 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F53L pathogenic mutation (also known as c.157T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 157. The phenylalanine at codon 53 is replaced by leucine, an amino acid with highly similar properties. This alteration, which is also known as p.F33L, was first reported in a Polish-American individual who developed symptoms of autonomic dysfunction and neuropathy at 53 years of age; a sural nerve biopsy showed the presence of amyloid and immunohistochemistry revealed transthyretin (Ii S et al. Neurology, 1991 Jun;41:893-8). This variant has been identified in individuals of Polish, Swedish, Ashkenazi Jewish, and Asian ancestry with symptoms of familial amyloidotic polyneuropathy (Harding J et al. Biochim Biophys Acta. 1991; 1097(3):183-6; Holmgren G et al. Amyloid. 2005; 12(3):189-92; Leibou L et al. Isr Med Assoc J. 2012; 14(11):662-5; Chen CH et al. J Formos Med Assoc. 2014; 113(8):575-6). A functional study of urea gradients found this alteration resulted in decreased conformational stability of the monomer molecule (Altland K et al. Electrophoresis. 2007; 28(12):2053-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel 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	0.81
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.60	.;T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M;M;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	.;D;.;.
REVEL	Pathogenic	0.79
Sift	Benign	0.033	.;D;.;.
Sift4G	Benign	0.25	.;T;T;D
Polyphen		0.84	P;P;.;.
Vest4		0.46, 0.61, 0.63
MutPred		0.76		Gain of MoRF binding (P = 0.1578);Gain of MoRF binding (P = 0.1578);Gain of MoRF binding (P = 0.1578);Gain of MoRF binding (P = 0.1578);
MVP		1.0
MPC		0.61
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.95
Mutation Taster		=2/98	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

Other links and lift over

dbSNP: rs121918068; hg19: chr18-29172946;