Submissions for variant NM_000371.4(TTR):c.328C>A (p.His110Asn) (rs121918074)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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,Children's Hospital of Eastern Ontario	RCV000770556	SCV000902004	benign	Cardiomyopathy	2018-06-11	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego	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
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000857889	SCV001151525	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, 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,Illumina	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,London Health Sciences Centre	RCV001173306	SCV001336390	likely benign	Charcot-Marie-Tooth disease		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