Single allele AND Dilated cardiomyopathy 1G

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 4, 2017
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:: RCV000677985.2

Allele description [Variation Report for Single allele]

Genes:

LOC129935182:ATAC-STARR-seq lymphoblastoid active region 16807 [Gene]
LOC129935183:ATAC-STARR-seq lymphoblastoid active region 16808 [Gene]
LOC129935184:ATAC-STARR-seq lymphoblastoid active region 16809 [Gene]
LOC129935185:ATAC-STARR-seq lymphoblastoid active region 16810 [Gene]
LOC129935186:ATAC-STARR-seq lymphoblastoid active region 16811 [Gene]
LOC129935181:ATAC-STARR-seq lymphoblastoid silent region 12151 [Gene]
LOC126806420:BRD4-independent group 4 enhancer GRCh37_chr2:179401104-179402303 [Gene]
LOC126806422:BRD4-independent group 4 enhancer GRCh37_chr2:179440205-179441404 [Gene]
LOC126806421:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179407630-179408829 [Gene]
LOC126806423:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179443309-179444508 [Gene]
LOC126806424:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179456337-179457536 [Gene]
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
PLEKHA3:pleckstrin homology domain containing A3 [Gene - OMIM - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

HGVS:

NC_000002.12:g.178504948_178606784del
NC_000002.11:g.179369675_179471511del

Condition(s)

Name:: Dilated cardiomyopathy 1G (CMD1G)
Identifiers:: MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000804140	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	criteria provided, single submitter (ACMG CNV Guidelines, 2011)	Likely pathogenic (Dec 4, 2017)	maternal	provider interpretation	PubMed (2) [See all records that cite these PMIDs] 22335739, 21681106

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000804140

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

criteria provided, single submitter

(ACMG CNV Guidelines, 2011)

Likely pathogenic
(Dec 4, 2017)

maternal

provider interpretation

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	maternal	unknown	not provided	not provided	not provided	not provided	not provided	provider interpretation

Citations

PubMed

Truncations of titin causing dilated cardiomyopathy.

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, et al.

N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.

PubMed [citation]

PMID:: 22335739
PMCID:: PMC3660031

American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants.

Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee..

Genet Med. 2011 Jul;13(7):680-5. doi: 10.1097/GIM.0b013e3182217a3a.

PubMed [citation]

PMID:: 21681106

Details of each submission

From Geisinger Autism and Developmental Medicine Institute, Geisinger Health System, SCV000804140.2

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

Description

This deletion was identified in a patient with a history of intellectual disability, autism spectrum disorder, and insomnia. A mitochondrial disorder has previously been suspected. The deletion includes a portion of the TTN and PLEKHA3 genes. PLEKHA3 has not been associated with a known condition at this time. TTN, however, is expressed in the skeletal and cardiac muscles and has been associated with several conditions including isolated cardiomyopathies, limb-girdle muscular dystrophy, proximal myopathy with early respiratory involvement, Salih myopathy, and Tibial muscular dystrophy. The deletion includes exons 229-313 of the TTN gene. This deletion includes the A and M bands of the protein and this particular deletion has not been reported previously. Deletions and loss of function variants in TTN that impact the A and M bands, such as the deletion found in this patient, are associated with isolated cardiomyopathies. 18-25% of dilated cardiomyopathies have been associated with such TTN variants. Deletions such as this have also been detected in healthy individuals (Herman et al. 2012). This could be due to reduced penetrance, however. The variant was also detected in the patient's mother who does not have a reported history of cardiomyopathy.

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

Last Updated: Oct 14, 2023

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