18-31595247-C-G

Variant names:

• chr18-31595247-C-G
• NM_000371.4:c.328C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000371.4(TTR):​c.328C>G​(p.His110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H110N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.227

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 Uncertain_significance. Variant got 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31595247-C-G is Pathogenic according to our data. Variant chr18-31595247-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1524375.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr18-31595247-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.328C>G	p.His110Asp	missense_variant	Exon 3 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.328C>G	p.His110Asp	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.328C>G	p.His110Asp	missense_variant	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.232C>G	p.His78Asp	missense_variant	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.354C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:1

Mar 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1524375). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. This variant is also known as p.His90Asp. This missense change has been observed in individual(s) with clinical features of hereditary transthyretin-mediated amyloidosis (PMID: 17554795, 25430583; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 110 of the TTR protein (p.His110Asp). -

Cardiovascular phenotype Uncertain:1

Dec 29, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H110D variant (also known as c.328C>G), located in coding exon 3 of the TTR gene, results from a C to G substitution at nucleotide position 328. The histidine at codon 110 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in multiple amyloidosis cohorts, including two affected individuals from the same family (Benson MD et al. Muscle Nerve, 2007 Oct;36:411-23; Jimenez-Zepeda VH et al. Amyloid, 2015 Mar;22:26-30; Carr AS et al. J Neurol Neurosurg Psychiatry, 2016 Jun;87:620-7; Rowczenio D et al. Hum Mutat, 2019 01;40:90-96). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.86	D;D;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.1	L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	.;D;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0080	.;D;.;.
Sift4G	Benign	0.20	.;T;T;T
Polyphen		0.33	B;B;.;.
Vest4		0.42, 0.46, 0.37
MutPred		0.42		Gain of catalytic residue at H110 (P = 0.0892);Gain of catalytic residue at H110 (P = 0.0892);Gain of catalytic residue at H110 (P = 0.0892);Gain of catalytic residue at H110 (P = 0.0892);
MVP		0.99
MPC		1.1
ClinPred		0.80	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-29175210;