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

gnomAD frequency: 0.00017  dbSNP: rs138657343

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000996672	SCV000209376	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Reported in an individual with HCM who also harbored a variant in the MYBPC3 gene in published literature (Viswanathan et al., 2017); however, no segregation studies were described; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27249223, 31659433, 29121657, 32674397)
Ambry Genetics	RCV000246043	SCV000319110	likely benign	Cardiovascular phenotype	2019-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV000474573	SCV000541955	uncertain significance	Familial amyloid neuropathy	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the TTR protein (p.Arg5His). This variant is present in population databases (rs138657343, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TTR-related conditions (PMID: 29121657, 32674397). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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, Mass General Brigham 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 e.org; dbSNP rs138657343).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769524	SCV000900919	uncertain significance	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000996672	SCV001151521	likely benign	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000474573	SCV001284895	uncertain significance	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). 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000996672	SCV002049134	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	The TTR c.14G>A; p.Arg5His variant (rs138657343) is reported in the literature in an individual affected with hereditary transthyretin amyloidosis (Auer-Grumbach 2020) as well as in an individual with hypertrophic cardiomyopathy (Viswanathan 2017). This variant is also reported in ClinVar (Variation ID: 181697). It is found in the general population with an overall allele frequency of 0.013% (36/282806 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). However, given the lack of clinical and functional data, the significance of the p.Arg5His variant is uncertain at this time. References: Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. PMID: 32674397. Viswanathan SK et al. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS One. 2017 Nov 9;12(11):e0187948. PMID: 29121657.
Revvity Omics, Revvity	RCV000996672	SCV003819860	uncertain significance	not provided	2019-10-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416024	SCV004118327	uncertain significance	TTR-related condition	2023-06-01	criteria provided, single submitter	clinical testing	The TTR c.14G>A variant is predicted to result in the amino acid substitution p.Arg5His. This variant was reported in an individual with Cardiomyopathy, hypertrophic (Table S3 Viswanathan et al. 2017. PubMed ID: 29121657) and in an individual with hereditary amyloidosis (Auer-Grumbach et al. 2020. PubMed ID: 32674397). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-29171879-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV000996672	SCV004224478	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000474573	SCV001338823	uncertain significance	Familial amyloid neuropathy	2019-08-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000996672	SCV001744173	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000996672	SCV001923180	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000996672	SCV001931590	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000996672	SCV001958504	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000996672	SCV001969846	likely benign	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000474573	SCV002818401	not provided	Familial amyloid neuropathy		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 11-03-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.