rs11541790

Variant names:

• chr18-31592956-C-T
• rs11541790
• NM_000371.4:c.130C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.130C>T​(p.Pro44Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,212 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44L) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.03
• Publications: 6 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 19 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr18-31592957-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 948928.Status of the report is criteria_provided_single_submitter, 1 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, 0.993
• PP5: Variant 18-31592956-C-T is Pathogenic according to our data. Variant chr18-31592956-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 181693.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.130C>T	p.Pro44Ser	missense_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.130C>T	p.Pro44Ser	missense_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00000497 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 10, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro44Ser (c.130C>T) in the TTR gene. Under alternate nomenclature this variant is also called p.Pro24Ser. The variant has been seen in at least 1 unrelated case of familial amyloidosis, segregating with disease in a total of 3 affected family members . Dr. Merrill Benson's group reported this variant in a family with carpal tunnel syndrome, peripheral neuropathy and cardiomyopathy (Uemichi et al 1995). It was identified in a 67yo male with amyloid cardiomyopathy and a family history of cardiac amyloidosis who died at age 69 due to cardiac failure. The variant was also present in two other affected relatives. One died at 72 of heart problems and autopsy showed cardiac amyloidosis. The authors do not report on identification of the specific type of amyloid species. Uemichi and colleagues concluded that the clinical features of this variant include relatively late onset, slow progression of disease and absence of vitreous opacification. I could find no other published reports of this variant, however, I did find a few unpublished reports. This includes ann online listing of TTR variants reported to the Familial Amyloidotic Polyneuropathy World Transplant Registry and Domino Liver Transplant Registry lists this variant associated with liver and heart transplants at Mayo in 2005 and in a French hospital in 2011 (http://www.fapwtr.org/mutation.htm). I also found a report that this variant showed equivocal results in studies on tafamdis, possibly due to prolonged storage of patient plasma (Merlini et al 2013). I also found a public letter to the FDA written by a patient with amyloidosis and this variant. This variant has been reported primarily in the USA and the phenotype correlations to this genotype include cardiomyopathy, carpal tunnel syndrome and peripheral neuropathy. This variant hasn't been implicated in cardiac-only amyloidosis (Gene Reviews, 2013). Other variants have been reported in association with disease at nearby codons (Asp38Asn, Asp38Gly, Asp38Glu, Val40Ile, Ser43Asn, Ala45Ser, Ala45Thr, Val48Met). In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 44 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 12/6/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 12/6/13). -

Jul 21, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) 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 1661C>T, Pro24Ser. Computational tools predict that this variant is damaging. -

Jul 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Presentation is often cardiac-dominant but also includes carpal tunnel syndrome and peripheral neuropathy (PMID: 20301373); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(P24S); This variant is associated with the following publications: (PMID: 10842707, 31583185, 31343285, 29984770, 17503405, 28494620, 38117424, 24650283, 19618439, 38661598, 31713445, 31728576, 9487333, 34740514, 32861330, 7643356, 26656838, 30243104, 30553273, 31587306, 33309574, 37610765, 20301373) -

Jul 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyloidosis, hereditary systemic 1 Pathogenic:2

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 44 of the TTR protein (p.Pro44Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 7643356, 24650283). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro24Ser. ClinVar contains an entry for this variant (Variation ID: 181693). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 17503405). For these reasons, this variant has been classified as Pathogenic. -

May 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTR c.130C>T (p.Pro44Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251632 control chromosomes. c.130C>T has been observed in multiple individuals affected with Transthyretin Amyloidosis (Uemichi_1995, Dasari_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Altland_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17503405, 24650283, 7643356). ClinVar contains an entry for this variant (Variation ID: 181693). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Dec 17, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P44S pathogenic mutation (also known as c.130C>T and p.P24S), located in coding exon 2 of the TTR gene, results from a C to T substitution at nucleotide position 130. The proline at codon 44 is replaced by serine, an amino acid with similar properties. This alteration was described in a 67-year-old individual with amyloid cardiomyopathy, bilateral carpal tunnel, and paresthesias of the lower limbs. Three additional affected family members and four asymptomatic family members also carried this alteration (Uemichi T et al. J. Med. Genet., 1995 Apr;32:279-81). This alteration was also detected in multiple individuals from a hereditary amyloidosis cohort (Dasari S et al. J. Proteome Res., 2014 May;13:2352-8; Koike H et al. J. Neurol. Sci., 2018 11;394:99-106). Electrophoretic analysis suggested that this alteration caused instability of the functional tetramer (Altland K et al. Electrophoresis, 2007 Jun;28:2053-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.;.
PhyloP100		6.0
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.3	.;D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	.;D;.;.
Sift4G	Uncertain	0.057	.;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.89, 0.86, 0.76
MutPred		0.95		Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.99
Mutation Taster		=25/75	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: rs11541790; hg19: chr18-29172919;