ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.14G>A (p.Arg5His) (rs138657343)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159430 SCV000209376 uncertain significance not specified 2017-06-23 criteria provided, single submitter clinical testing The R5H variant of uncertain significance in the TTR gene has not been published as a pathogenicvariant or been reported as a benign variant to our knowledge. R5H has been identified in conjunctionwith additional cardiogenetic variants in several individuals referred for cardiomyopathy genetictesting at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack ofclinical information provided and/or insufficient participation by informative family members. Thisvariant was not observed with any significant frequency in the NHLBI Exome Sequencing Project, orin the Exome Aggregation Consortium (ExAC). Nevertheless, the R5H variant is a conservativeamino acid substitution, which is not likely to impact secondary protein structure as these residuesshare similar properties. Moreover, this substitution occurs at a position not conserved, and in silicoanalysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or benign.
Ambry Genetics RCV000246043 SCV000319110 likely benign Cardiovascular phenotype 2019-09-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000474573 SCV000541955 uncertain significance Amyloidogenic transthyretin amyloidosis 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 5 of the TTR protein (p.Arg5His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs138657343, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181697). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000159430 SCV000710973 likely benign not specified 2017-08-23 criteria provided, single submitter clinical testing p.Arg5His in exon 1 of TTR: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >15 mammals, including chimpanzee, have a histidine (His) at this position. Thi s variant has been identified in 21/126636 European chromosomes, including 1 hom ozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut; dbSNP rs138657343).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769524 SCV000900919 likely benign Cardiomyopathy 2019-02-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996672 SCV001151521 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000474573 SCV001284895 uncertain significance 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173539 SCV001336629 likely benign Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000474573 SCV001338823 uncertain significance Amyloidogenic transthyretin amyloidosis 2019-08-29 no assertion criteria provided clinical testing

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