19-55137191-G-C

Variant names:

• chr19-55137191-G-C
• rs780372739
• NM_003283.6:c.523C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003283.6(TNNT1):​c.523C>G​(p.Arg175Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TNNT1 NM_003283.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNNT1 Gene-Disease associations (from GenCC):

• nemaline myopathy 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• nemaline myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• nemaline myopathy 5C, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003283.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	NM_003283.6	MANE Select	c.523C>G	p.Arg175Gly	missense	Exon 11 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.523C>G	p.Arg175Gly	missense	Exon 11 of 14	NP_001119604.1
	TNNT1	NM_001126133.3		c.490C>G	p.Arg164Gly	missense	Exon 10 of 13	NP_001119605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.523C>G	p.Arg175Gly	missense	Exon 11 of 14	ENSP00000467176.1
	TNNT1	ENST00000291901.12	TSL:1	c.523C>G	p.Arg175Gly	missense	Exon 11 of 14	ENSP00000291901.8
	TNNT1	ENST00000356783.9	TSL:1	c.490C>G	p.Arg164Gly	missense	Exon 10 of 13	ENSP00000349233.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523C>G (p.R175G) alteration is located in exon 11 (coding exon 10) of the TNNT1 gene. This alteration results from a C to G substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Nemaline myopathy 5 Uncertain:1

Nov 17, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TNNT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 175 of the TNNT1 protein (p.Arg175Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.3	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.068	T
Polyphen		0.95	P
Vest4		0.48
MutPred		0.64		Loss of methylation at K174 (P = 0.0492)
MVP		0.97
MPC		0.81
ClinPred		0.95	D
GERP RS		3.1
PromoterAI		-0.095	Neutral
Varity_R		0.53
gMVP		0.45
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780372739; hg19: chr19-55648559;