ClinVar Genomic variation as it relates to human health

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.

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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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)

Variant summary: The variant c.130C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in approximately 121572 control chromosomes from the large and broad populations of ExAC. This variant has been reported in multiple ATTR-affected individuals including the evidence of cosegregation with disease (Uemichi_J Med Genet_ 1995, Dasari_JPR_2014, etc.). Functional study showed that variant has the weakening effect on the monomer-monomer contact (Altland_Electrophoresis_2007). One clinical laboratory has classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.

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.

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).