NM_003280.3(TNNC1):c.65C>A (p.Ala22Glu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 25, 2022
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:: RCV003019136.2

Allele description [Variation Report for NM_003280.3(TNNC1):c.65C>A (p.Ala22Glu)]

NM_003280.3(TNNC1):c.65C>A (p.Ala22Glu)

Gene:

TNNC1:troponin C1, slow skeletal and cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.1

Genomic location:

Preferred name:

NM_003280.3(TNNC1):c.65C>A (p.Ala22Glu)

HGVS:

NC_000003.12:g.52452243G>T
NG_008963.1:g.6799C>A
NG_033112.1:g.1736G>T
NG_033112.2:g.1641G>T
NG_099590.1:g.261G>T
NM_003280.3:c.65C>AMANE SELECT
NP_003271.1:p.Ala22Glu
NP_003271.1:p.Ala22Glu
LRG_378t1:c.65C>A
LRG_378:g.6799C>A
LRG_378p1:p.Ala22Glu
NC_000003.11:g.52486259G>T
NM_003280.2:c.65C>A

Protein change:

A22E

Molecular consequence:

NM_003280.3:c.65C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1Z (CMD1Z)
Identifiers:: MONDO: MONDO:0012745; MedGen: C2678475; Orphanet: 154; OMIM: 611879

Name:: Hypertrophic cardiomyopathy 13
Synonyms:: Familial hypertrophic cardiomyopathy 13; TNNC1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0013195; MedGen: C2750472; OMIM: 613243

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003310645	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32815737, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003310645

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 25, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients.

Pua CJ, Tham N, Chin CWL, Walsh R, Khor CC, Toepfer CN, Repetti GG, Garfinkel AC, Ewoldt JF, Cloonan P, Chen CS, Lim SQ, Cai J, Loo LY, Kong SC, Chiang CWK, Whiffin N, de Marvao A, Lio PM, Hii AA, Yang CX, Le TT, et al.

Circ Genom Precis Med. 2020 Oct;13(5):424-434. doi: 10.1161/CIRCGEN.119.002823. Epub 2020 Aug 20.

PubMed [citation]

PMID:: 32815737
PMCID:: PMC7676617

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003310645.2

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

Description

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32815737). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 22 of the TNNC1 protein (p.Ala22Glu).

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

Last Updated: Feb 28, 2024

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