rs138657343

chr18-31591916-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000371.4(TTR):c.14G>A(p.Arg5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:9 O:1
• Conservation: PhyloP100: -0.437

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03921768).
• BP6: Variant 18-31591916-G-A is Benign according to our data. Variant chr18-31591916-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181697.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=4, not_provided=1}. Variant chr18-31591916-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.14G>A	p.Arg5His	missense_variant	1/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.14G>A	p.Arg5His	missense_variant	1/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251406 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135866

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.000128 AC XY: 93 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2023	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) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 09, 2019	- -

Familial amyloid neuropathy Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 29, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 21, 2023

- -

TTR-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

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. -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	2.9
Dann	Benign	0.87
DEOGEN2	Benign	0.20	T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.48	N;N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
Polyphen		0.0020	B;B;.;.
Vest4		0.024, 0.086, 0.074
MVP		0.82
MPC		0.58
ClinPred		0.017	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138657343; hg19: chr18-29171879; COSMIC: COSV99379427;