Submissions for variant NM_000371.4(TTR):c.262A>T (p.Ile88Leu)

gnomAD frequency: 0.00004  dbSNP: rs121918085

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014388	SCV000823548	pathogenic	Amyloidosis, hereditary systemic 1	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the TTR protein (p.Ile88Leu). This variant is present in population databases (rs121918085, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1786038, 22745357, 26428663, 26537620). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13446). 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%. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014388	SCV000967004	likely pathogenic	Amyloidosis, hereditary systemic 1	2020-07-27	criteria provided, single submitter	clinical testing	The p.Ile88Leu variant in TTR (also described as p.Ile68Leu in the literature) has been identified in >20 individuals with clinical features of hereditary transthyretin amyloidosis (ATTR; Almeida 1991 PMID: 1786038, Hesse 1993 PMID: 8038017, Salvi 2003 PMID: 14640031, Perfetto 2011 PMID: 21540676, Ihse 2013 PMID: 23713495, Rapezzi 2013 PMID: 22745357, Cappelli 2016 PMID: 26428663, Damy 2016 PMID: 26537620, Iorio 2017 PMID: 28635949, Maurizi 2020 PMID: 31371117) and segregated with disease in at least 5 individuals from at least one family (Rapezzi 2013 PMID: 22745357). Clinical features in affected individuals included a mostly cardiac amyloidosis phenotype, with some neurologic and mixed cardiac/neurologic phenotypes. This variant has also been reported by another clinical laboratory in ClinVar (Variation ID 13446) and has been identified in 0.004% (5/129164) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Results from an in vitro functional study using electrophoretic analyses to assess the role of this variant show that while variant p.Ile88Leu TTR monomer could be clearly distinguished from its wild type counterpart, it did not result in a reduced conformational stability of both TTR monomers and tetramers (Altland 2007 PMID: 17503405). Therefore, the clinical significance of these results is uncertain. Additionally, 7 mammals (squirrel, antelope, cow, goat, sheep, Tasmanian devil, opossum) carry a Leucine (Leu) at this position with moderate nearby amino acid conservation and additional computational tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATTR based upon presence in multiple affected individuals and segregation studies. ACMG/AMP criteria applied: PS4, PM2, PP1_Moderate, BP4.
Athena Diagnostics	RCV001288934	SCV001476392	pathogenic	not provided	2024-05-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is statistically more frequent in affected individuals than in the general population (PMID: 25997105, 25636337, 26208957, 26537620, 31103217, 31502881). This variant associates with autosomal dominant TTR-related amyloid cardiomyopathy (PMID 9017939), formerly known as familial amyloidotic cardiomyopathy (FAC), in multiple families (PMID: 8038017, 17062380, 22745357, 26428663). In some published literature, this variant is referred to as p.Ile68Leu.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001288934	SCV002047731	likely pathogenic	not provided	2021-05-14	criteria provided, single submitter	clinical testing	The TTR c.262A>T; p.Ile88Leu variant (rs121918085), also known as p.Ile88Leu, is reported in the literature in multiple individuals affected with hereditary transthyretin amyloidosis (Damy 2016, Ihse 2013, Iorio 2017, Mauzrizi 2020) and segregated with disease in at least one family (Rapezzi 2013). This variant is also reported in ClinVar (Variation ID: 13446). This variant is found in the non-Finnish European population with an allele frequency of 0.0018% (5/129164 alleles) in the Genome Aggregation Database. The isoleucine at codon 88 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.554). Based on available information, this variant is considered to be likely pathogenic. References: Damy T et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016 Jun 14;37(23):1826-34. PMID: 26537620. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. PMID: 23713495. Iorio A et al. Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet. 2017 Sep;25(9):1055-1060. PMID: 28635949. Maurizi N et al. Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy. Int J Cardiol. 2020 Feb 1;300:191-195. PMID: 31371117. 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.
Mendelics	RCV000014388	SCV002519921	pathogenic	Amyloidosis, hereditary systemic 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426503	SCV002741229	pathogenic	Cardiovascular phenotype	2023-06-14	criteria provided, single submitter	clinical testing	The p.I88L pathogenic mutation (also known as c.262A>T and I68L), located in coding exon 3 of the TTR gene, results from an A to T substitution at nucleotide position 262. The isoleucine at codon 88 is replaced by leucine, an amino acid with highly similar properties. This pathogenic mutation was first described in a German male with cardiac amyloidosis and dysaesthesia in both hands (Almeida MR et al. Basic Res Cardiol. 1991; 86(6):567-71). A large multicenter study in the Italian population found this pathogenic mutation to be the third most common TTR mutation, and the most common TTR mutation with a predominantly cardiac phenotype; it was identified in 27 individuals from 22 families, 23 of whom had a predominantly cardiac phenotype, 3 of whom had a predominantly neurologic phenotype, and 1 of whom had a mixed phenotype (Rapezzi C et al. Eur Heart J. 2013; 34(7):520-8). One functional study showed this mutation has minimal effect to the stability of the protein structure; however, this analysis does not capture how mutations in TTR result in pathology (Atland K et al. Electrophoresis 2007 Jun;28(12):2053-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002476966	SCV002800788	likely pathogenic	Hyperthyroxinemia, dystransthyretinemic; Amyloidosis, hereditary systemic 1; Carpal tunnel syndrome 1	2022-04-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001288934	SCV002820807	likely pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies showed that although mutant protein could be distinguished from wild type protein, it showed no change in conformational stability compared to wild type (Altland et al., 2007); This variant is associated with the following publications: (PMID: 31371117, 1786038, 8038017, 14640031, 21540676, 22745357, 23713495, 26428663, 26537620, 28635949, 30638075, 31589614, 36444226, 17503405, 24767411, 18544157, 34746851, 30070416, 24184229, 34622675, 30683924, 33844361, 28188196, 34658264, 34828392, 34047656, 35717381, 28494620)
Revvity Omics, Revvity	RCV001288934	SCV003816010	likely pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001288934	SCV004225049	pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	PP4, PM2, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014388	SCV005888316	pathogenic	Amyloidosis, hereditary systemic 1	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: TTR c.262A>T (p.Ile88Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251440 control chromosomes. c.262A>T has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (Almeida_1991, Salvi_2003, Rapezzi_2011, Rapezzi_2013). These data indicate that the variant is very likely to be associated with disease. 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: 15123043, 17503405, 17577688, 21540676, 1786038, 15645642, 12228058, 21679902, 14640031, 19752327, 8038017, 22745357). ClinVar contains an entry for this variant (Variation ID: 13446). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000014388	SCV000034637	pathogenic	Amyloidosis, hereditary systemic 1	1993-08-01	no assertion criteria provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000014388	SCV004015006	pathogenic	Amyloidosis, hereditary systemic 1	2023-05-11	no assertion criteria provided	clinical testing