rs1555631390

Variant names:

• chr18-31595128-G-GTGAGTC
• rs1555631390
• NM_000371.4:c.212_217dupAGTCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000371.4(TTR):​c.212_217dupAGTCTG​(p.Glu71_Ser72dup) variant causes a disruptive inframe insertion 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0170
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 40 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000371.4.
• PP5: Variant 18-31595128-G-GTGAGTC is Pathogenic according to our data. Variant chr18-31595128-G-GTGAGTC is described in ClinVar as Pathogenic. ClinVar VariationId is 545518.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.212_217dupAGTCTG	p.Glu71_Ser72dup	disruptive_inframe_insertion	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.212_217dupAGTCTG	p.Glu71_Ser72dup	disruptive_inframe_insertion	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.212_217dupAGTCTG	p.Glu71_Ser72dup	disruptive_inframe_insertion	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.116_121dupAGTCTG	p.Glu39_Ser40dup	disruptive_inframe_insertion	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.238_243dupAGTCTG		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

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:1

Mar 16, 2018

Amyloidosis Center, Boston University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A 37 year old African American man presented with sensorimotor polyneuropathy, and myopathy in his lower extremities. Deposits of variant TTR were detected in the right shin skin using tandem mass spectrometry. A fat aspirate was Congo red positive for amyloid deposits, the patient's brother was also diagnosed with amyloidosis by sural nerve biopsy. Following nine months of diflunisal treatment (250mg/daily), the patient demonstrated progression of sensorimotor polyneuropathy, and also autonomic neuropathy. Diflunisal treatment was stopped due to lack of efficacy. The patient was found to have a six base pair duplication in TTR exon 3 (c.212_217dupAGTCTG) by DNA sequencing of the TTR gene. The patient died from recurrent aspiration pneumonia, debilitating peripheral and autonomic neuropathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.017
Mutation Taster		=62/38	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555631390; hg19: chr18-29175091;