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NM_000371.4(TTR):c.280G>C (p.Asp94His) AND Familial amyloid neuropathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 25, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000647355.16

Allele description [Variation Report for NM_000371.4(TTR):c.280G>C (p.Asp94His)]

NM_000371.4(TTR):c.280G>C (p.Asp94His)

Gene:
TTR:transthyretin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_000371.4(TTR):c.280G>C (p.Asp94His)
Other names:
p.D94H:GAC>CAC
HGVS:
  • NC_000018.10:g.31595199G>C
  • NG_009490.1:g.8433G>C
  • NM_000371.4:c.280G>CMANE SELECT
  • NP_000362.1:p.Asp94His
  • NP_000362.1:p.Asp94His
  • LRG_416t1:c.280G>C
  • LRG_416:g.8433G>C
  • LRG_416p1:p.Asp94His
  • NC_000018.9:g.29175162G>C
  • NM_000371.3:c.280G>C
  • P02766:p.Asp94His
Protein change:
D94H
Links:
UniProtKB: P02766#VAR_007581; dbSNP: rs730881164
NCBI 1000 Genomes Browser:
rs730881164
Molecular consequence:
  • NM_000371.4:c.280G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial amyloid neuropathy
Synonyms:
Amyloidosis Transthyretin related; Amyloid polyneuropathy transthyretin related; TTR amyloid neuropathy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007100; MedGen: C2751492; Orphanet: 85447; Orphanet: 85451; OMIM: 105210

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000769147Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 25, 2024) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Viswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, Sadayappan S.

PLoS One. 2017;12(11):e0187948. doi: 10.1371/journal.pone.0187948.

PubMed [citation]
PMID:
29121657
PMCID:
PMC5679632

Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.

Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B.

J Med Genet. 2021 Apr;58(4):284-288. doi: 10.1136/jmedgenet-2019-106641. Epub 2020 May 6.

PubMed [citation]
PMID:
32376792
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000769147.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 94 of the TTR protein (p.Asp94His). This variant is present in population databases (rs730881164, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hATTR amyloidosis and/or hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 29121657, 32376792, 34658264; Invitae). ClinVar contains an entry for this variant (Variation ID: 181695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024