18-31595169-T-C

Position:

• chr18-31595169-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000371.4(TTR):​c.250T>C​(p.Phe84Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F84I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.44

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595169-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 18-31595169-T-C is Pathogenic according to our data. Variant chr18-31595169-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595169-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.250T>C	p.Phe84Leu	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.250T>C	p.Phe84Leu	missense_variant	3/4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.250T>C	p.Phe84Leu	missense_variant	5/6			ENSP00000497927.1
TTR	ENST00000610404.5	c.154T>C	p.Phe52Leu	missense_variant	3/4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.276T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	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; This variant is associated with the following publications: (PMID: 22592564, 24395461, 31589614, 27350016, 34668655, 26428663, 22745357, 35095067, 34658264, 34207092, 2046936, 30811423, 23279339, 8721565, 28188196, 28635949) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 11, 2023	The TTR c.250T>C; p.Phe84Leu variant (rs121918091), also known as Phe64Leu, is published in the medical literature in numerous individuals and families with transthyretin-related amyloidosis (Benson 2007, Ii 1991, Rapezzi 2013, Russo 2012). The variant is listed in the ClinVar database (Variation ID: 13453) but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 84 is highly conserved and other amino acid substitutions at this codon (c.252T>G; p.Phe84Leu and c.251T>C; p.Phe84Ser) are reported in individuals with transthyretin-related amyloidosis (Benson 2007, Rapezzi 2013, Uemichi 1999). Considering available information, the c.250T>C; p.Phe84Leu variant is classified as pathogenic. References: Benson MD and Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. PMID: 17554795. Ii S et al. Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology. 1991 Jun;41(6):893-8. PMID: 2046936. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. PMID: 22745357. Russo M et al. Transthyretin-related familial amyloidotic polyneuropathy: description of a cohort of patients with Leu64 mutation and late onset. J Peripher Nerv Syst. 2012 Dec;17(4):385-90. PMID: 23279339. Uemichi T et al. Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64. Arch Neurol. 1999 Sep;56(9):1152-5. PMID: 10488818. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with hereditary transthyretin-related amyloidosis. In some published literature, this variant is referred to as p.Phe64Leu. This variant results in the same amino acid change as another variant considered to be pathogenic (c.252T>G). Assessment of experimental evidence suggests this variant results in abnormal protein function. Patient-derived samples containing this variant displayed decreased stability of TTR tetramers (PMID 17503405). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

Amyloidosis, hereditary systemic 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the TTR protein (p.Phe84Leu). This variant is present in population databases (rs121918091, gnomAD 0.0009%). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2046936, 8721565, 22745357, 23279339, 28635949). This variant is also known as p.Phe64Leu. ClinVar contains an entry for this variant (Variation ID: 13453). 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%. This variant disrupts the p.Phe84 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10488818, 15820680). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2016	Variant summary: The TTR c.250T>C (p.Phe84Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121202 control chromosomes. The variant has been reported in numerous affected individuals in the literature and has been classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

Carpal tunnel syndrome;C2750824:Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.250T>C (p.F84L) alteration is located in exon 3 (coding exon 3) of the TTR gene. This alteration results from a T to C substitution at nucleotide position 250, causing the phenylalanine (F) at amino acid position 84 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251440) total alleles studied. The highest observed frequency was 0.001% (1/113734) of European (non-Finnish) alleles. This variant was first reported in an individual with peripheral neuropathy, autonomic symptoms, and cardiac and GI involvement with amyloid deposits confirmed on biopsy (Ii, 1991). This variant has been reported in multiple families from Italy and may be associated with disease onset in the sixth to seventh decade (Ferlini, 1996; Russo, 2012; Luigetti, 2013; Cortese, 2017; Iorio, 2017). Type B fibrils, which consist of full-length peptides and can have an impact on the phenotype of the disease, have been found in individuals with this variant (Suhr, 2019). This nucleotide position is highly conserved in available vertebrate species. Functional analysis suggests this variant results in a decrease in the stability of the protein structure (Altland, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.5	L;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	.;D;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.067	.;T;.;.
Sift4G	Benign	0.16	.;T;D;T
Polyphen		0.99	D;D;.;.
Vest4		0.43, 0.45, 0.85
MutPred		0.65		Gain of catalytic residue at F84 (P = 0.0868);Gain of catalytic residue at F84 (P = 0.0868);Gain of catalytic residue at F84 (P = 0.0868);Gain of catalytic residue at F84 (P = 0.0868);
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.97

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: rs121918091; hg19: chr18-29175132;