NM_000371.4(TTR):c.130C>T (p.Pro44Ser) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000159421.10

Allele description [Variation Report for NM_000371.4(TTR):c.130C>T (p.Pro44Ser)]

NM_000371.4(TTR):c.130C>T (p.Pro44Ser)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.130C>T (p.Pro44Ser)

Other names:

p.P44S:CCT>TCT

HGVS:

NC_000018.10:g.31592956C>T
NG_009490.1:g.6190C>T
NM_000371.4:c.130C>TMANE SELECT
NP_000362.1:p.Pro44Ser
NP_000362.1:p.Pro44Ser
LRG_416t1:c.130C>T
LRG_416:g.6190C>T
LRG_416p1:p.Pro44Ser
NC_000018.9:g.29172919C>T
NM_000371.3:c.130C>T
P02766:p.Pro44Ser

Protein change:

P44S

Links:

UniProtKB: P02766#VAR_007551; dbSNP: rs11541790

NCBI 1000 Genomes Browser:

rs11541790

Molecular consequence:

NM_000371.4:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209367	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 19, 2024)	germline	clinical testing	Citation Link,
SCV000280558	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Feb 10, 2014)	germline	clinical testing
SCV004229418	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jul 21, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 7643356, 30243104, 31728576, 31583185, 19618439, 29984770, 28494620, 31587306, 17503405, 24101373, 26656838, 30553273, 24650283, 31343285, 31713445, 33309574, 30169969, 32861330, 34740514, 26467025
SCV005046486	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A new transthyretin variant (Ser 24) associated with familial amyloid polyneuropathy.

Uemichi T, Gertz MA, Benson MD.

J Med Genet. 1995 Apr;32(4):279-81.

PubMed [citation]

PMID:: 7643356
PMCID:: PMC1050375

The morphology of amyloid fibrils and their impact on tissue damage in hereditary transthyretin amyloidosis: An ultrastructural study.

Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Sakurai T, Shimohata T, Katsuno M, Sobue G.

J Neurol Sci. 2018 Nov 15;394:99-106. doi: 10.1016/j.jns.2018.09.011. Epub 2018 Sep 12.

PubMed [citation]

PMID:: 30243104

See all PubMed Citations (21)

Details of each submission

From GeneDx, SCV000209367.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280558.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	not provided	not provided

From Athena Diagnostics, SCV004229418.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV005046486.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 28, 2025

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