rs76992529

Variant names:

• chr18-31598655-G-A
• rs76992529
• NM_000371.4:c.424G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31598655-G-A
• chr18-31598655-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 17P and 3B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4 BS1_Supporting BS2_Supporting

The ENST00000237014.8(TTR):​c.424G>A​(p.Val142Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,614,082 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060031: This variant has been shown to render the TTR protein complex unstable, causing misfolding and deposits in the myocardium (Jiang 2001, Askansas 2003).; SCV000284750: Experimental studies have shown that this missense change affects TTR function (PMID:15820680, 17503405, 18276611).; SCV001142480: Functional studies demonstrate that Val122Ile affect TTR protein function (PMID:18276611).; SCV001441407: Functional studies demonstrated that the p.(Val142Ile) variant confer amyloidogenic properties via causing conformational changes and reducing the stability of the physiologic TTR tetramer [PMIDs: 17503405, 18276611].; SCV002061278: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:12874414, 27758856, 27720586, 11752443) - PS3."; SCV002754521: Functional studies have shown that this variant alters TTR protein function (PMID:11752443, 12874414, 15820680, 17503405, 22184092, 24474780) (PS3).; SCV003841759: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:11752443).; SCV004046301: Functional studies demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID:11752443, 18276611).; SCV005901567: Multiple functional studies have demonstrated that this variant results in reduced tetramer stability and increased amyloid fibril formation (Jiang et al., 2001; Askanas et al., 2003).; SCV006557253: Experimental studies have shown that this missense change renders the TTR complex unstable, leading to greater formation of amyloid fibrils compared to wild type protein.; SCV000209380: Cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations (Askanas et al., 2003); Renders the TTR complex unstable, leading to unfolding and lower tetramer stability (Jiang et al., 2001).; SCV000605508: Functional studies have demonstrated instability of the variant tetramer protein (Altland 2007, Jiang 2001, Sekijima 2005, Steward 2008), and suggest the variant predisposes to accumulation of amyloid beta peptide as well as causes vacuolar degeneration leading to decreased viability of cultured skeletal muscle (Askanas 2003).; SCV000616219: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:11752443, 35903975); SCV000318173: This mutation has been reported to decrease the stability of the transthyretin tetramer and lower the kinetic barrier for tetramer dissociation, which increases the extent and rate of amyloid fibril formation (Jiang X et al. PNAS. 2001;98(26):14943-8).; SCV000996263: Experimental studies have shown that this missense change weakens the stability of the TTR tetramer protein complexes (PMID:15820680, 17503405, 18276611).; SCV005418460: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV004046214: Experimental studies have shown that this variant weakens the stability of TTR tetramer protein complexes in plasma and cerebrospinal fluid (PMID:15820680, 17503405, 18276611).; SCV004116698: "In vitro experimental studies indicate this variant impacts protein function (Jiang et al. 2001. PubMed ID: 11752443; Sekijma et al. 2005. PubMed ID: 15820680; Altland et al. 2007. PubMed ID: 17503405)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V142A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: TTR ENST00000237014.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:51 O:1
• Conservation: PhyloP100: 3.22
• Publications: 825 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

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060031: This variant has been shown to render the TTR protein complex unstable, causing misfolding and deposits in the myocardium (Jiang 2001, Askansas 2003).; SCV000284750: Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 17503405, 18276611).; SCV001142480: Functional studies demonstrate that Val122Ile affect TTR protein function (PMID: 18276611).; SCV001441407: Functional studies demonstrated that the p.(Val142Ile) variant confer amyloidogenic properties via causing conformational changes and reducing the stability of the physiologic TTR tetramer [PMIDs: 17503405, 18276611].; SCV002061278: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12874414, 27758856, 27720586, 11752443) - PS3."; SCV002754521: Functional studies have shown that this variant alters TTR protein function (PMID: 11752443, 12874414, 15820680, 17503405, 22184092, 24474780) (PS3).; SCV003841759: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11752443).; SCV004046301: Functional studies demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID: 11752443, 18276611).; SCV005901567: Multiple functional studies have demonstrated that this variant results in reduced tetramer stability and increased amyloid fibril formation (Jiang et al., 2001; Askanas et al., 2003).; SCV006557253: Experimental studies have shown that this missense change renders the TTR complex unstable, leading to greater formation of amyloid fibrils compared to wild type protein.; SCV000209380: Cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations (Askanas et al., 2003); Renders the TTR complex unstable, leading to unfolding and lower tetramer stability (Jiang et al., 2001).; SCV000605508: Functional studies have demonstrated instability of the variant tetramer protein (Altland 2007, Jiang 2001, Sekijima 2005, Steward 2008), and suggest the variant predisposes to accumulation of amyloid beta peptide as well as causes vacuolar degeneration leading to decreased viability of cultured skeletal muscle (Askanas 2003).; SCV000616219: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11752443, 35903975); SCV000318173: This mutation has been reported to decrease the stability of the transthyretin tetramer and lower the kinetic barrier for tetramer dissociation, which increases the extent and rate of amyloid fibril formation (Jiang X et al. PNAS. 2001;98(26):14943-8).; SCV000996263: Experimental studies have shown that this missense change weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611).; SCV005418460: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV004046214: Experimental studies have shown that this variant weakens the stability of TTR tetramer protein complexes in plasma and cerebrospinal fluid (PMID: 15820680, 17503405, 18276611).; SCV004116698: "In vitro experimental studies indicate this variant impacts protein function (Jiang et al. 2001. PubMed ID: 11752443; Sekijma et al. 2005. PubMed ID: 15820680; Altland et al. 2007. PubMed ID: 17503405)."
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in ENST00000237014.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31598656-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1333466.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 hereditary ATTR amyloidosis, heart conduction disease, familial amyloid neuropathy, ATTRV122I amyloidosis, amyloidosis, hereditary systemic 1.
• PP5: Variant 18-31598655-G-A is Pathogenic according to our data. Variant chr18-31598655-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009103388). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00467 (711/152230) while in subpopulation AFR AF = 0.0165 (687/41538). AF 95% confidence interval is 0.0155. There are 5 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 711 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000237014.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.424G>A	p.Val142Ile	missense	Exon 4 of 4	NP_000362.1	P02766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.424G>A	p.Val142Ile	missense	Exon 4 of 4	ENSP00000237014.4	P02766
	TTR	ENST00000649620.1		c.424G>A	p.Val142Ile	missense	Exon 6 of 6	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.424G>A	p.Val142Ile	missense	Exon 6 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 152112 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 251408 AF XY: 0.000670

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461852 Hom.: 3 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 727234

African (AFR) AF: 0.0175 AC: 586 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112006

Other (OTH) AF: 0.000911 AC: 55 AN: 60394

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152230 Hom.: 5 Cov.: 33 AF XY: 0.00421 AC XY: 313 AN XY: 74432

African (AFR) AF: 0.0165 AC: 687 AN: 41538

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00176 Hom.: 6

Bravo AF: 0.00560

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 167

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
23	-	-	Amyloidosis, hereditary systemic 1 (24)
17	-	-	not provided (17)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 (2)
2	-	-	TTR-related disorder (2)
1	-	-	Amyloidosis (1)
1	-	-	ATTRV122I amyloidosis (1)
1	-	-	Cardiomyopathy (1)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.48	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.94
MPC		0.39
ClinPred		0.065	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.79
Mutation Taster		=66/34	disease causing (ClinVar)

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: rs76992529; hg19: chr18-29178618; COSMIC: COSV99030963; COSMIC: COSV99030963;