Submissions for variant NM_000371.4(TTR):c.337-3T>C

gnomAD frequency: 0.00001  dbSNP: rs774027595

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214127	SCV000272866	uncertain significance	not specified	2016-01-28	criteria provided, single submitter	clinical testing	The c.337-3T>C variant in TTR has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/66424 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs77 4027595). This variant is located in the 3' splice region. Computational tools d o not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.337-3T>C variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540460	SCV000648567	uncertain significance	Amyloidosis, hereditary systemic 1	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the TTR gene. It does not directly change the encoded amino acid sequence of the TTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs774027595, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 229596). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000621559	SCV000740160	uncertain significance	Cardiovascular phenotype	2023-03-23	criteria provided, single submitter	clinical testing	The c.337-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 4 in the TTR gene. This variant has been detected in an individual with cardiomyopathy (Skrahina V et al. Ann Med, 2021 Dec;53:1787-1796). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000786264	SCV001861951	benign	not provided	2016-02-18	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786264	SCV000925015	uncertain significance	not provided	2017-11-10	no assertion criteria provided	provider interpretation	c.337-3T>C (intronic) in intron 3 of the TTR gene (NM_000371.3; chr18-29178528-T-C) SCICD Classification: variant of uncertain significance based on lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Lab Classification (Invitae): variant of uncertain significance Gene-level evidence: TTR: There is enough evidence in the literature to associate the TTR gene with cardiovascular disease: TTR encodes transthyretin, a tetramer that circulates in the serum and cerebrospinal fluid to transport other molecules, such as thyroxine throughout the body. Pathogenic variants in TTR lead to amyloidosis, or aggregation and deposition of the transthyretin proteins into organs such as the heart. Amyloid deposition often leads to polyneuropathy and cardiomyopathy. TTR-amyloidosis is often a late-onset disorder. There are several common founder variants in TTR that lead to TTR-amyloidosis, some of which have genotype-phenotype correlations. Case data (not including our patient): 1 ClinVar: seen in one patient at the Laboratory for Molecular Medicine, classified as a VUS Cases in the literature: none reported This variant co-occurred with an LP variant in TTN in one of our patients with DCM. Segregation data: none reported Functional data: none reported Splice data (splice variants only): There is data that variants at the -3 position does not alter splicing patterns in most cases and is not highly conserved like canonical splice sites +/- 1 and 2 are (Buratti et al 2007). Conservation data: The thymine located at the third base of intron 3 is not conserved across species. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in Latino population: 0.0029%. The variant was reported online in 3 of 138,410 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 63,214 individuals of European descent and 1 of 17,202 individuals of Latino descent (MAF=0.0029%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.