ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.280G>C (p.Asp94His) (rs730881164)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725937 SCV000209374 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTR gene. The D94H variant, also denoted as D74H by alternative nomenclature, has been reported as a common variant in the German population as it was identified in 7 out of 4,000 pregnant women with no family history of amyloidosis or thyroid disorder (Uemichi et al., 1994). The D94H variant has been observed in multiple individuals referred for cardiomyopathy genetic testing at GeneDx, however, segregation data are thus far uninformative and some individuals harbored additional cardiogenetic variants. The D94H variant is observed 13/277180 (0.005%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The D94H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725937 SCV000340651 uncertain significance not provided 2016-04-05 criteria provided, single submitter clinical testing
Invitae RCV000647355 SCV000769147 uncertain significance Amyloidogenic transthyretin amyloidosis 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 94 of the TTR protein (p.Asp94His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs730881164, ExAC 0.004%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy, however in that individual additional variants in other genes associated with cardiomyopathy were detected (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181695). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765411 SCV000896693 uncertain significance Carpal tunnel syndrome; Dystransthyretinemic euthyroidal hyperthyroxinemia; Amyloidogenic transthyretin amyloidosis 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725937 SCV001151523 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173300 SCV001336384 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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