rs397516392

Positions:

• chr15-63064126-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001018005.2(TPM1):​c.835A>C​(p.Asn279His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N279D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.32

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 128 pathogenic changes around while only 5 benign (96%) in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.835A>C	p.Asn279His	missense_variant	9/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.835A>C	p.Asn279His	missense_variant	9/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	Variant classified as Uncertain Significance - Favor Pathogenic. The Asn279His v ariant in TPM1 has been identified in homozygosity in 1 proband with RCM tested by our laboratory and has not been identified in large and broad European Americ an and African American populations by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). This low frequency is consistent with a disease ca using role but insufficient to establish this with confidence. This variant was present in heterozygosity in two family members with HCM but also in a 67 year o ld unaffected family member (this individual). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. This data support s pathogenicity of the Asn279His variant and raises the possibility that homozyg osity and heterozygosity are associated with different phenotypic outcomes (RCM, HCM). However, the available data is not yet sufficient to conclude this with confidence. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 19, 2011	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. c.835A>C (p.Asn279His) in the TPM1 gene. We have seen this in a patient with restrictive cardiomyopathy who was homozygous (Caleshu et al 2011). Her father and sister are heterozygous for this variant and are both diagnosed with HCM. Her mother, who also carries one copy of this variant does not have a phenotype of HCM or RCM. In silico analysis with PolyPhen-2 predicts the variant to be benign. The asparagine at codon 279 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with at nearby codons. A variant in a neighboring codon (Met281Thr) has been reported in association with Hypertrophic Cardiomyopathy (van Driest et al 2003) In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 279 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 5/27/13). This variant was absent in 600 caucasian published controls. Harvard lab did not give control data. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/23/13). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 23, 2017

- -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
CardioboostCm	Benign	0.0066
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.84
DEOGEN2	Uncertain	0.79	.;D;.;.;.;D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.3	L;L;L;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.6	N;N;.;.;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.46	T;T;.;.;.;T
Sift4G	Benign	0.15	T;T;.;.;.;T
Polyphen		0.0	.;B;B;.;.;.
Vest4		0.87
MutPred		0.56		Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);.;.;
MVP		0.97
ClinPred		0.58	D
GERP RS		5.8
Varity_R		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516392; hg19: chr15-63356325;