ClinVar Genomic variation as it relates to human health

Variant summary: The c.417G>A variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 5/5 in silico tools via Alamut the gain of a cryptic splice acceptor site, however, the significance of these predictions has not been supported with functional studies. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.28%, predominantly observed in the East Asian subpopulation at a frequency of 1.9% including 2 homozygous occurrences. This frequency greatly exceeds the maximal expected allele frequency for a pathogenic variant in TTR (0.003%), suggesting this is a benign polymorphism found primarily in population(s) of East Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One reputable clinical lab has classified the variant as "benign". Due to the synonymous nature of the variant along with the high allele frequency in the general population, this variant has been classified as Benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Thr139Thr in exon 4 of TTR: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue, is not located within th e splice consensus sequence, and it has been identified in 0.4% (9/2250) of chro mosomes from a broad, though clinically and racially unspecified population (dbS NP rs2276382).

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr139Thr (aka c.7349 G>A, c.417G>A, p.Thr119Thr). Given the type of variant and the presence in general population samples matching the patient's ancestry we consider this a variant of unknown significance, probably benign. This variant has not been reported in association with amyloidosis. It has been seen at low frequency in samples approximating the general population (see details below). Per their ClinVar submission, the Laboratory for Molecular Medicine classifies this variant as benign since it does not change the amino acid sequence, it is not located in the splice consensus sequence, and it is present as a rare variant in population samples (SCV000060030). This is a synonymous single nucleotide variant. It does not change the amino acid at this codon. Per the Athena report, five in silico splicing prediction algorithms predict the variant to create a new splice acceptor site. However, the original splice acceptor is unchanged so it is unclear what the impact would be on splicing. Essentially all TTR variants associated with amyloidosis are missense variants (see http://www.ibmc.up.pt/mjsaraiva/ttrmut.html, http://amyloidosismutations.com/attr.html, http://www.bumc.bu.edu/msr/ttr-database/ttr-mutations/). Considering the mechanism of disease in ATTR we would not expect either a synonymous variant or a null variant (via nonsense-mediated decay) to cause disease. It possible that a variant affecting could cause amyloidosis however this seems unlikely and to our knowledge it has not been reported. In total the variant has been seen in 10 of 7592 individuals from publicly available population datasets, with the highest frequency in patient's of Asian ancestry (which matches the patient's ancestry). It is listed in dbSNP (rs2276382) with submitted data from the following population datasets. The variant was reported online in 1 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of June 12, 2014). The phenotype of that individual 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. It was also observed in 9 of 1089 individuals in phase 1 of the 1000 genomes project including 5 of 197 Chinese individuals, 3 of 89 Japanese individuals, and 1 of 64 Mexican individuals. It looks like it has also been observed in the ClinSeq cohort, which is also a general population cohort.