NM_001018005.2(TPM1):c.115-6T>C AND Hypertrophic cardiomyopathy 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 6, 2021
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:: RCV002470336.1

Allele description [Variation Report for NM_001018005.2(TPM1):c.115-6T>C]

NM_001018005.2(TPM1):c.115-6T>C

Gene:

TPM1:tropomyosin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.2

Genomic location:

Preferred name:

NM_001018005.2(TPM1):c.115-6T>C

HGVS:

NC_000015.10:g.63044021T>C
NG_007557.1:g.6383T>C
NG_131178.1:g.603T>C
NM_000366.6:c.115-6T>C
NM_001018004.2:c.115-6T>C
NM_001018005.2:c.115-6T>CMANE SELECT
NM_001018006.2:c.115-6T>C
NM_001018007.2:c.240+190T>C
NM_001018020.2:c.240+190T>C
NM_001301244.2:c.240+190T>C
NM_001365776.1:c.115-6T>C
NM_001365777.1:c.115-6T>C
NM_001365778.1:c.241-6T>C
NM_001365779.1:c.115-6T>C
LRG_387t1:c.115-6T>C
LRG_387:g.6383T>C
NC_000015.9:g.63336220T>C
NM_001018005.1:c.115-6T>C
NR_176348.1:n.28T>C
NR_176349.1:n.28T>C

Molecular consequence:

NM_000366.6:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001018004.2:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001018005.2:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001018006.2:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001018007.2:c.240+190T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001018020.2:c.240+190T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001301244.2:c.240+190T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001365776.1:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001365777.1:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001365778.1:c.241-6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001365779.1:c.115-6T>C - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hypertrophic cardiomyopathy 3
Synonyms:: Familial hypertrophic cardiomyopathy 3; TPM1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0007267; MedGen: C1861863; OMIM: 115196

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002767099	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31270709, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002767099

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1.

Moraczewska J.

J Muscle Res Cell Motil. 2020 Mar;41(1):39-53. doi: 10.1007/s10974-019-09532-y. Epub 2019 Jul 3. Review.

PubMed [citation]

PMID:: 31270709
PMCID:: PMC7109180

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767099.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, it has been suggested that hypertrophic cardiomyopathy missense variants result in a gain of function whilst dilated cardiomyopathy variants result in a loss of function (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0219 - This variant is deep intronic in alternative transcripts. However, this variant is located in the splice region in the transcript most highly expressed in heart (GTEx) and predominantly reported in ClinVar. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - Abnormal splicing is not predicted, however the affected nucleotide is highly conserved. (I) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2022

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