ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.130C>T (p.Pro44Ser) (rs11541790)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159421 SCV000209367 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing The Pro44Ser mutation in the TTR gene has been reported in a family with cardiac amyloidosis and cardiomyopathy (Uemichi T et al., 1995). Pro44Ser (reported as Pro24Ser due to alternate nomenclature) was identified in a male with amyloid cardiomyopathy and a family history of cardiac amyloidosis who died at age 69 due to cardiac failure (Uemichi T et al., 1995). This study identified Pro44Ser in three other affected relatives in this family. Mutations in nearby residues (Val40Ile, Ser43Asn, Ala45Ser, Ala45Thr) have been reported in association with cardiac amyloidosis, further supporting the functional importance of this region of the protein. Furthermore, Pro44Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Pro44Ser in the TTR gene is interpreted as a disease-causing mutation.
Integrated Genetics/Laboratory Corporation of America RCV000560691 SCV000696614 pathogenic Amyloidogenic transthyretin amyloidosis 2016-03-23 criteria provided, single submitter clinical testing 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.
Invitae RCV000560691 SCV000648563 uncertain significance Amyloidogenic transthyretin amyloidosis 2018-02-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 44 of the TTR protein (p.Pro44Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with familial amyloid polyneuropathy in a single family (PMID: 7643356). This variant is also known as Ser24 in the literature. ClinVar contains an entry for this variant (Variation ID: 181693). Experimental studies have shown that this missense change affects protein stability (PMID: 17503405). In summary, this variant has uncertain impact on TTR function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159421 SCV000280558 likely pathogenic not provided 2014-02-10 no assertion criteria provided 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).

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