rs138065384
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBS2_Supporting
The NM_000371.4(TTR):āc.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
Consequence
NM_000371.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251466Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135908
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727150
GnomAD4 genome AF: 0.000158 AC: 24AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74456
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2025 | In 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 submitter | clinical testing | Athena Diagnostics | Feb 12, 2025 | The 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 submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2024 | PM5, PS4_moderate - |
Amyloidosis, hereditary systemic 1 Pathogenic:1Benign:1
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 - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2025 | - - |
not specified Uncertain:1Benign:1
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. - |
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. - |
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 | - - |
Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2024 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at