chr18-31592974-G-A

Variant names:

• chr18-31592974-G-A
• rs28933979
• NM_000371.4:c.148G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3 PM1 PM5 PP2 PP3 PP5_Very_Strong BS2_Supporting

The NM_000371.4(TTR):​c.148G>A​(p.Val50Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000203972: in vitro functional studies provide some evidence that this variant impacts protein function by reducing conformational stability (Yi 1991 PMID:1992765, Altland 2007 PMID:17503405, Goncalves 2014 PMID:24800914)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V50L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:39 O:1
• Conservation: PhyloP100: 2.83
• Publications: 944 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000203972: in vitro functional studies provide some evidence that this variant impacts protein function by reducing conformational stability (Yi 1991 PMID: 1992765, Altland 2007 PMID: 17503405, Goncalves 2014 PMID: 24800914).; SCV000541951: Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 23080516, 24601850, 25550818).; SCV001423810: Transgenic mice carrying the p.Val50Met variant show higher amyloid deposition in the gastrointestinal tract, renal glomeruli, myocardium, small vascular walls, and thyroid with advancing age, which is consistent with findings from patient autopsy reports (Yi et al. 1991). Goncalves et al. (2014) showed a higher TTR expression, tissue specific deposition in nerves, reduced inflammatory response, and impaired regenerative process in injured nerves of transgenic p.Val50Met mice compared to their wild type counterparts.; SCV002061162: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25519307, 26088020) - .PS3_moderate."; SCV002521706: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25519307, 26088020).; SCV002570305: Experimental studies demonstrate that this missense variant significantly affects protein stability. In addition, transgenic mice containing this variant showed amyloid deposition and an inflammatory response similar to human familial transthyretin amyloidosis.; SCV005418256: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006084822: Multiple functional studies have demonstrated that this variant disrupts TTR protein function (Altland et al., 2007; Gonçalves et al., 2014; Jesus et al., 2016).; SCV000616207: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17503405, 15820680, 35903975); SCV000884814: Functional studies suggest the variant refolds from monomers to tetramers at a slower rate compared to wildtype (Jesus 2016), has decreased stability in the folded state (Altland 2007), and impairs the inflammatory response necessary for nerve regeneration (Goncalves 2014). PMID: 27589730 PMID: 17503405 PMID: 24800914; SCV004745647: Functional studies found this variant disrupts protein function (Altland et al. 2007. PubMed ID: 17503405; Jesus et al. 2016. PubMed ID: 27589730).
• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000371.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31592974-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13440.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 18-31592974-G-A is Pathogenic according to our data. Variant chr18-31592974-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 7 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: NM_000371.4. 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.148G>A	p.Val50Met	missense	Exon 2 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.148G>A	p.Val50Met	missense	Exon 2 of 4	ENSP00000237014.4	P02766
	TTR	ENST00000649620.1		c.148G>A	p.Val50Met	missense	Exon 4 of 6	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.148G>A	p.Val50Met	missense	Exon 4 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251462 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000581 AC: 85 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727214

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111956

Other (OTH) AF: 0.000232 AC: 14 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000443 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
15	-	-	Amyloidosis, hereditary systemic 1 (16)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	TTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.99
MPC		1.3
ClinPred		0.60	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.97
Mutation Taster		=11/89	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: rs28933979; hg19: chr18-29172937;