rs138065384

Positions:

chr18-31593016-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBS2_Supporting

The NM_000371.4(TTR):c.190T>C(p.Phe64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F64S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4B:2

Conservation

PhyloP100: 2.65

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000371.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31593017-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.17767632).

BS2

High AC in GnomAd4 at 24 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.190T>C	p.Phe64Leu	missense_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8 linkuse as main transcript	c.190T>C	p.Phe64Leu	missense_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251466

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000615

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:

0.0000137

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

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

AF:

0.000158

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000270

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2016	A variant of uncertain significance was identified in the TTR gene. The F64L variant has previously been reported in association with cardiac amyloidosis (Connors et al., 2009; Reddi et al., 2014; Rowczenio et al., 2014). F64L (reported as F44L due to alternate nomenclature) was initially reported in an African American patient with amyloidosis who also harbored a second missense variant on the opposite TTR allele (in trans) (Connors et al., 2009). The F64L (reported as F44L) variant has also been reported in a Caucasian individual with cardiac involvement in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014). Additionally, this variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000204704.5; Landrum et al., 2016). The F64L variant was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other missense variants in nearby residues (W61L, E62G, E62D, A65S, A65T, A65D) and at the same residue (F64Y, F64S) have been reported in the Human Gene Mutation Database in association with amyloidosis, amylodotic polyneuropathy, and cardiomyopathy (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. In addition, the F64L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species, and in silico algorithms are inconsistent in predicting an effect of this variant on protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2023	The frequency of this variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with hereditary transthyretin-related amyloidosis, including individuals with cardiac transthyretin amyloidosis. In Italy, it has been suggested to be one of the most common variants associated with FAP (familial amyloidotic polyneuropathy) (PMID: 36289657). Multiple affected individuals have been reported with missense changes at this codon, suggesting this variant also causes disease. This variant is also referred to as F44L and F84L in published literature. -

Amyloidosis, hereditary systemic 1

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jul 03, 2023	ACMG Citeria: PM2, PM5, PP5, PS3_M; Variant found in a heterozygous state -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 06, 2021	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe64Leu variant in TTR has been reported in at least 17 individuals with amyloidosis, including one homozygote and one compound heterozygote for another pathogenic TTR missesne variant which suggests that this variant may not be the primary cause of disease in this individual.(Ferlini 1996 PMID: 8721565, Comenzo 2006 PMID: 16439680, Connors 2009 PMID: 19781421, Cappellari 2011 PMID: 21692911, Klein 2011 PMID: 20937937, Rapezzi 2011 PMID: 21679902, Luigetti 2012 PMID: 22592564). It has also been reported in two individuals with hypertrophic cardiomyopathy (Walsh 2017 PMID: 27532257 Hoss 2020 PMID: 32150461, LMM data). It has been identified in 0.06% (14/24960) of African American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 178280). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Altland 2007 PMID: 17503405); however, these types of assays may not accurately represent biological function. Additional variants involving this codon (p.Phe64Ser and p.Phe64Tyr) have been identified in individuals with amyloidosis. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain: ACMG/AMP Criteria applied: PS4, PS3_Supporting. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2024	Variant summary: TTR c.190T>C (p.Phe64Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251466 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Isolated Cardiac Amyloidosis phenotype (5e-05). c.190T>C has been reported in the literature in individuals affected with Isolated Cardiac Amyloidosis or cardiomyopathy, as well as unaffected carriers (e.g. Connors_2009, Walsh_2017, Musumeci_2020). These reports do not provide unequivocal conclusions about association of the variant with Isolated Cardiac Amyloidosis. Co-occurrence with another pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile, Connors_2009), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Altland_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19781421, 17503405, 27532257, 31864976). ClinVar contains an entry for this variant (Variation ID: 178280). Based on the evidence outlined above, the variant was classified as likely benign. -

Charcot-Marie-Tooth disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 08, 2020

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The p.F64L variant (also known as c.190T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 190. The phenylalanine at codon 64 is replaced by leucine, an amino acid with highly similar properties. This variant (also described as p.F44L) has been reported in an individual with amyloidosis, who also had an additional TTR variant detected (Connors LH et al. Am. Heart J., 2009 Oct;158:607-14). This variant was also reported in one individual from a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Benign

0.42

DEOGEN2

Uncertain

0.60

D;D;T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.78

.;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

0.32

N;N;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.090

.;N;.;.

REVEL

Uncertain

0.53

Sift

Benign

0.57

.;T;.;.

Sift4G

Benign

0.65

.;T;T;T

Polyphen

0.17

B;B;.;.

Vest4

0.37, 0.41, 0.39

MutPred

0.62

Gain of disorder (P = 0.1562);Gain of disorder (P = 0.1562);Gain of disorder (P = 0.1562);Gain of disorder (P = 0.1562);

MVP

0.99

MPC

0.61

ClinPred

0.054

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over