18-31598602-G-A

Position:

• chr18-31598602-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Moderate BP6 BS2_Supporting

The NM_000371.4(TTR):​c.371G>A​(p.Arg124His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:11
• Conservation: PhyloP100: 1.25

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.11815715).
• BP6: Variant 18-31598602-G-A is Benign according to our data. Variant chr18-31598602-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13458.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr18-31598602-G-A is described in Lovd as [Pathogenic]. Variant chr18-31598602-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 48 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.371G>A	p.Arg124His	missense_variant	4/4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2907C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.371G>A	p.Arg124His	missense_variant	4/4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.371G>A	p.Arg124His	missense_variant	6/6			ENSP00000497927.1
TTR	ENST00000610404.5	c.275G>A	p.Arg92His	missense_variant	4/4	5		ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00827

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000792 AC: 199 AN: 251350 Hom.: 1 AF XY: 0.000736 AC XY: 100 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0104

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1461860 Hom.: 2 Cov.: 31 AF XY: 0.000191 AC XY: 139 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00549

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00810

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 10529370, 15820680, 10772944, 16911959) -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2016	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. -

Amyloidosis, hereditary systemic 1 Pathogenic:1 Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 22, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Benign, 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). 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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2013	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) -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 28, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2017

This alteration is classified as 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	0.061
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	0.31
DANN	Benign	0.34
DEOGEN2	Uncertain	0.60	D;D;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.76	.;T;T;T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-3.5	N;N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	4.3	.;N;.;.
REVEL	Uncertain	0.50
Sift	Benign	1.0	.;T;.;.
Sift4G	Benign	1.0	.;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.16, 0.30, 0.18
MVP		0.81
MPC		0.58
ClinPred		0.018	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.63

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: rs121918095; hg19: chr18-29178565;