18-31595139-G-C

Variant names:

• chr18-31595139-G-C
• rs1555631393
• NM_000371.4:c.220G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000371.4(TTR):​c.220G>C​(p.Glu74Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.80
• Publications: 2 publications found

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]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 34 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595139-GA-CT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1712259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 18-31595139-G-C is Pathogenic according to our data. Variant chr18-31595139-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 448842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.220G>C	p.Glu74Gln	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.220G>C	p.Glu74Gln	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.220G>C	p.Glu74Gln	missense_variant	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.124G>C	p.Glu42Gln	missense_variant	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.246G>C		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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 06, 2025

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In some published literature, this variant is referred to as p.Glu54Gln. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Cardiovascular phenotype Pathogenic:1

Feb 01, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E74Q variant (also known as c.220G>C and E54Q), located in coding exon 3 of the TTR gene, results from a G to C substitution at nucleotide position 220. The glutamic acid at codon 74 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in two individuals with restrictive cardiomyopathy, biopsies documenting the presence of amyloid via Congo red staining, and a family history of a parent with cardiomyopathy. One individual also had progressive peripheral sensory motor polyneuropathy and autonomic dysfunction while the second individual had carpal tunnel syndrome; her parent with cardiomyopathy also had severe sensorimotor neuropathy (Rowczenio DM et al. Hum. Mutat., 2014 Sep;35:E2403-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Sep 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as Glu54Gln. This sequence change replaces glutamic acid with glutamine at codon 74 of the TTR protein (p.Glu74Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 25044787, 27519456, 31718691, 32000831). ClinVar contains an entry for this variant (Variation ID: 448842). 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 disrupts the p.Glu74 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PhyloP100		5.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	.;N;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0080	.;D;.;.
Sift4G	Uncertain	0.045	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.72, 0.73, 0.87
MutPred		0.70		Loss of glycosylation at S70 (P = 0.0598);Loss of glycosylation at S70 (P = 0.0598);Loss of glycosylation at S70 (P = 0.0598);Loss of glycosylation at S70 (P = 0.0598);
MVP		1.0
MPC		1.3
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.98
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1555631393; hg19: chr18-29175102;