Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000152541 | SCV000201745 | uncertain significance | not specified | 2017-03-30 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.His110Asn (al so reported as p.His90Asn) variant in TTR has been reported in 1 individual with recurrent cerebral hemorrhages, but did not segregate in an affected family mem ber (Bersano 2009). In addition, it has been reported in 1 individual with famil ial amyloidotic polyneuropathy, who also carried a second established pathogenic TTR variant (Skare 1989, Skare 1991, Skare 1994). It has also been identified b y our laboratory in 2 individuals with HCM, 1 individual with LVH, and in 1 indi vidual with DCM, who also carried 2 MYBPC3 variants sufficient to explain diseas e. This variant has also been identified in several unaffected individuals (Sara iva 1991, Alves 1997, Conners 2003, Schwarzman 2004) and in 0.12% (78/66708) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs121918074). Computational prediction tools and conservat ion analysis suggest that the p.His110Asn variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, while the clinical significance of the p.His110Asn variant is uncertain, t hese data suggest that it is more likely to be benign. |
Invitae | RCV000014369 | SCV000554847 | benign | Amyloidogenic transthyretin amyloidosis | 2019-12-31 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000621211 | SCV000740246 | likely benign | Cardiovascular phenotype | 2017-10-30 | criteria provided, single submitter | clinical testing | In silico models in agreement (benign);Subpopulation frequency in support of benign classification |
CHEO Genetics Diagnostic Laboratory, |
RCV000770556 | SCV000902004 | benign | Cardiomyopathy | 2018-06-11 | criteria provided, single submitter | clinical testing | |
Center for Advanced Laboratory Medicine, |
RCV000852746 | SCV000995463 | likely benign | Heart failure | 2018-07-03 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000014369 | SCV001140873 | uncertain significance | Amyloidogenic transthyretin amyloidosis | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000857889 | SCV001151525 | uncertain significance | not provided | 2016-06-01 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000152541 | SCV001157560 | uncertain significance | not specified | 2019-04-12 | criteria provided, single submitter | clinical testing | The TTR c.328C>A; p.His110Asn variant (rs121918074), also published as His90Asn in the mature protein, is reported in the medical literature in an individual with recurrent cerebral hemorrhage but does not segregate with disease in the family (Bersano 2009). Additionally, the variant is reported in a family with amyloidosis who also carried a known pathogenic variant (Skare 1994). However, another variant in this codon, p.His110Asp, has been reported to segregate with disease in a large kindred with amyloid polyneuropathy (Jimenez-Zepeda 2015). The c.328C>A; p.His110Asn variant is reported in the ClinVar database with inconsistent classifications (Variation ID: 13427). The variant is reported with an allele frequency of up to 0.9% (90/10370 alleles) in the Ashkenazi Jewish population and 0.05% (155/282814 alleles) overall in the Genome Aggregation Database. The amino acid at this position is weakly conserved and computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the variant is uncertain at this time. References: Bersano A et al. Transthyretin Asn90 variant: amyloidogenic or non-amyloidogenic role. J Neurol Sci. 2009 Sep 15;284(1-2):113-5. Jimenez-Zepeda VH et al. A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred. Amyloid. 2015 Mar;22(1):26-30. Rowczenio D et al. Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. Hum Mutat. 2019 Jan;40(1):90-96. Skare J et al. Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis. Clin Genet. 1994 Jun;45(6):281-4. |
Illumina Clinical Services Laboratory, |
RCV000014369 | SCV001280820 | uncertain significance | Amyloidogenic transthyretin amyloidosis | 2017-04-28 | criteria provided, single submitter | clinical testing | 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. |
Molecular Genetics Laboratory, |
RCV001173306 | SCV001336390 | likely benign | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256816 | SCV001433273 | uncertain significance | Familial hypertrophic cardiomyopathy 1 | 2020-02-29 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000014369 | SCV000034618 | pathogenic | Amyloidogenic transthyretin amyloidosis | 1992-07-01 | no assertion criteria provided | literature only | |
Integrated Genetics/Laboratory Corporation of America | RCV000014369 | SCV000053247 | benign | Amyloidogenic transthyretin amyloidosis | 2015-05-14 | no assertion criteria provided | clinical testing |