ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.371G>A (p.Arg124His) (rs121918095)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Amyloidogenic transthyretin amyloidosis 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000014400 SCV001284995 benign Amyloidogenic transthyretin amyloidosis 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
OMIM RCV000014400 SCV000034649 pathogenic Amyloidogenic transthyretin amyloidosis 1999-10-22 no assertion criteria provided literature only

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