rs138065384

Variant summary

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

The NM_000371.4(TTR):ā€‹c.190T>Cā€‹(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 Pathogenic.

Frequency

Genomes: š‘“ 0.00016 ( 0 hom., cov: 32)
Exomes š‘“: 0.000014 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7B: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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a strand (size 7) in uniprot entity TTHY_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000371.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-31593017-T-C is described in Lovd as [Pathogenic].
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 rank MANE Protein UniProt
TTRNM_000371.4 linkc.190T>C p.Phe64Leu missense_variant Exon 2 of 4 ENST00000237014.8 NP_000362.1 P02766E9KL36

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTRENST00000237014.8 linkc.190T>C p.Phe64Leu missense_variant Exon 2 of 4 1 NM_000371.4 ENSP00000237014.4 P02766

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152160
Hom.:
0
Cov.:
32
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:
11
AN:
251466
Hom.:
0
AF XY:
0.0000441
AC XY:
6
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:
20
AN:
1461616
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
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:
24
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
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.:
0
Bravo
AF:
0.000162
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 30, 2025In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as F44L; This variant is associated with the following publications: (PMID: 19781421, 24184229, 16448460, 30638075, 33728572, 25044787, 30476936, 17503405, PiankovI2024[Preprint], 39655870, 32376792, 38523305, 36648052, VergaroG2023[Article], 32150461, 27532257, 31864976, 34410494, 28494620) -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 12, 2025The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (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. This variant is also referred to as F44L in published literature. Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 10, 2024PM5, PS4_moderate -
Amyloidosis, hereditary systemic 1 Pathogenic:1Benign:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Immunology and Genetics KaiserslauternJul 03, 2023ACMG Citeria: PM2, PM5, PP5, PS3_M; Variant found in a heterozygous state -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2025- -
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 20, 2024Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 06, 2021Variant 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. -
Charcot-Marie-Tooth disease Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJul 08, 2020- -
Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 03, 2024- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 19, 2024The 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
D
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
18
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
D
LIST_S2
Benign
0.78
.;T;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Uncertain
-0.035
T
MutationAssessor
Benign
0.32
N;N;.;.
PrimateAI
Uncertain
0.57
T
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
T
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.

Other links and lift over

dbSNP: rs138065384; hg19: chr18-29172979; API