Submissions for variant NM_003283.6(TNNT1):c.580G>A (p.Asp194Asn)

gnomAD frequency: 0.00019  dbSNP: rs141774400

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724813	SCV000225310	uncertain significance	not provided	2015-05-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000641949	SCV000414731	uncertain significance	Nemaline myopathy 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000724813	SCV000577078	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNT1 gene. The D194N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D194N variant is observed in 15/66,240 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D194N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and Asparagine has been observed at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000641949	SCV000763600	uncertain significance	Nemaline myopathy 5	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 194 of the TNNT1 protein (p.Asp194Asn). This variant is present in population databases (rs141774400, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TNNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 193862). 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 not expected to disrupt TNNT1 protein function. 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.
Revvity Omics, Revvity	RCV000724813	SCV003827712	uncertain significance	not provided	2023-11-17	criteria provided, single submitter	clinical testing