Submissions for variant NM_000371.4(TTR):c.371G>A (p.Arg124His)

gnomAD frequency: 0.00019  dbSNP: rs121918095

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152543	SCV000201748	benign	not specified	2013-11-19	criteria provided, single submitter	clinical testing	Arg124His in exon 4 of TTR: This variant is not expected to have clinical signi ficance because it is found in several other species including mammals and has b een identified in 2% (8/394) Chinese chromosomes by the 1000 Genomes Project (ht tp://www.1000genomes.org; dbSNP rs121918095). Arg124His in exon 4 of TTR (rs121 918095; allele frequency = 2%, 8/394)
Invitae	RCV000014400	SCV000284748	benign	Familial amyloid neuropathy	2024-01-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586735	SCV000696631	likely benign	not provided	2016-06-10	criteria provided, single submitter	clinical testing	Variant Summary: The TTR variant, c.371G>A (p.Arg124His) causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&Go and mutation taster not captured here due to low reliability index and p-value, respectively) predicting a "benign" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 79/121336 (1/1535 including 1 homozygote), predominantly in the Asian cohort, 79/25158 (1/322), which significantly exceeds the estimated expected allele frequency for a pathogenic TTR variant of 1/31948. Therefore, suggesting the variant is a common polymorphism found in population(s) of Asian origin. The variant of interest has been reported in affected individuals via multiple publications suggesting a benign nature for the variant or even a suppressive impact. A Japanese patient who was compound heterozygote expressing both R104H and V30M alleles did not exhibit the typical V30M FAP pathology displayed by V30M/WT heterozygotes. He exhibited increased levels of TTR and holo-RBP in serum relative to V30M/WT heterozygotes, suggesting that R104H suppresses V30M aggregation in vivo (Terazaki_1999). However, R104H compound heterozygotes expressing the aggressive mutation T59K from the second TTR allele presented with FAP pathology analogous to that characteristic of WT/T59K heterozygotes, suggesting that R104H may only suppress pathology in compound heterozygotes expressing mildly destabilizing TTR variants (Lim_2002). In vitro studies also support a benign or suppressor impact by the variant. Denaturation of TTR in V30M/R104H patient serum demonstrated that the R104H-containing tetramers were more resistant, suggesting that the R104H variant may stabilize the quaternary structure of TTR (Almeida_2000). These observations imply that the incorporation of R104H into heterotetramers comprised of an FAP-associated variant may stabilize the TTR structure, effectively preventing aggregation in vivo. In addition, authors suggest the variant of interest to act in a protective manner when as a complex allele with a mild TTR variant. In addition, multiple internal LCA samples report the variant to co-occur with other potentially pathogenic variants, MYH7 c.1273G>A (classified as likely pathgoenic ) and 2 reported with TTR variant, c.236C>A (p.Thr79Lys - classified as likely pathgoenic ). Multiple databases/clinical laboratories cite the variant with conflicting classifications, "pathogenic" or "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Likely Benign.
Ambry Genetics	RCV000621591	SCV000736086	benign	Cardiovascular phenotype	2017-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina	RCV000014400	SCV001284995	benign	Familial amyloid neuropathy	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170383	SCV001332960	benign	Cardiomyopathy	2017-11-28	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173296	SCV001336380	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000586735	SCV001881043	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10529370, 15820680, 10772944, 16911959)
OMIM	RCV000014400	SCV000034649	pathogenic	Familial amyloid neuropathy	1999-10-22	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000586735	SCV001917943	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000152543	SCV001929625	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586735	SCV001952116	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586735	SCV001963819	likely benign	not provided		no assertion criteria provided	clinical testing