Submissions for variant NM_000371.4(TTR):c.233T>A (p.Leu78His)

dbSNP: rs121918069

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159437	SCV000209383	pathogenic	not provided	2024-12-06	criteria provided, single submitter	clinical testing	Identified in association with amyloidosis and amyloidotic polyneuropathy; also reported as L58H due to alternative nomenclature (PMID: 20209591, 2613237, 26656838, 27724962, 34658264, 34461735, 33283548); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1644839, 17503405, 19602727, 22620962, 25526974, 2613237, 27724962, 17143887, 1656975, 25604431, 26656838, 34461735, 34658264, 33283548, 37014422, 20209591, 15820680)
Athena Diagnostics	RCV000159437	SCV000616212	pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014362	SCV000648564	pathogenic	Amyloidosis, hereditary systemic 1	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the TTR protein (p.Leu78His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2613237, 9196903, 17503405, 20209591, 25526974, 27724962). This variant is also known as p.Leu58His. ClinVar contains an entry for this variant (Variation ID: 13420). 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%. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 19602727). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014362	SCV000696619	pathogenic	Amyloidosis, hereditary systemic 1	2016-11-10	criteria provided, single submitter	clinical testing	Variant summary: The TTR c.233T>A (p.Leu78His) variant indicated to be located in the loop region (Cendron_2009) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. In addition, mutations in this residue (L78R) and in nearby residues (H76R, G77R, T79R, T79K) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and is a common TTR disease variant that is reported to be detected in >50 published cases, usually presenting with carpal tunnel syndrome and slowly progressing over two decades (Miller_2004). Multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000159437	SCV001746314	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000014362	SCV002526732	likely pathogenic	Amyloidosis, hereditary systemic 1	2022-05-31	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PM2_SUP, PM1_SUP, PM5, PS4_MOD
Ambry Genetics	RCV002444430	SCV002732384	pathogenic	Cardiovascular phenotype	2021-02-24	criteria provided, single submitter	clinical testing	The p.L78H variant (also known as c.233T>A and L58H), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 233. The leucine at codon 78 is replaced by histidine, an amino acid with similar properties. This alteration has been seen in multiple individuals with familial transthyretin amyloidosis whose symptoms generally included carpal tunnel syndrome, generalized neuropathy, amyloid deposits and positive congo red staining (Nichols WC, et al. Genomics 1989;5(3):535-40; Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Connors LH, et al. Biochim. Biophys. Acta 1998;1407(3):185-92; Ungerer MN et al. Amyloid, 2020 Dec;:1-9). In two additional studies, a small difference in the crystal structure of this variant compared with wild type was noted and the variant was shown to unfold 90% at 2.5M urea, indicating decreased conformation stability in the folded state (Altland K, et al. Electrophoresis 2007;28(12):2053-64; Cendron L, et al. J. Biol. Chem. 2009 Sep; 284(38):25832-41). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zhang J et al. Environ Sci Technol, 2018 10;52:11865-11874). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000159437	SCV005413286	pathogenic	not provided	2024-09-09	criteria provided, single submitter	clinical testing
OMIM	RCV000014362	SCV000034611	pathogenic	Amyloidosis, hereditary systemic 1	2001-02-27	no assertion criteria provided	literature only