NM_002667.5:c.43G>A

Variant names:

• chr6-118558964-G-A
• rs397516785
• NM_002667.5:c.43G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_002667.5(PLN):​c.43G>A​(p.Ala15Thr) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLN NM_002667.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.28
• Publications: 2 publications found

Genes affected

PLN (HGNC:9080): (phospholamban) The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

CEP85L Gene-Disease associations (from GenCC):

• lissencephaly 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_002667.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.62444 (below the threshold of 3.09). Trascript score misZ: -0.41852 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 18, intrinsic cardiomyopathy, dilated cardiomyopathy 1P, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 6-118558964-G-A is Pathogenic according to our data. Variant chr6-118558964-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44581.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLN	NM_002667.5	c.43G>A	p.Ala15Thr	missense_variant	Exon 2 of 2	ENST00000357525.6	NP_002658.1
CEP85L	NM_001042475.3	c.1020+6565C>T		intron_variant	Intron 3 of 12	ENST00000368491.8	NP_001035940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLN	ENST00000357525.6	c.43G>A	p.Ala15Thr	missense_variant	Exon 2 of 2	1	NM_002667.5	ENSP00000350132.5
CEP85L	ENST00000368491.8	c.1020+6565C>T		intron_variant	Intron 3 of 12	1	NM_001042475.3	ENSP00000357477.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1P Pathogenic:1

Dec 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 15 of the PLN protein (p.Ala15Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 24503780; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 44581). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

May 01, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Ala15Thr va riant has not been reported in the literature, but has been identified in 1 out of >1000 probands tested by our laboratory and segregated with disease in one af fected family member. This variant has not been identified in a very large and b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS); this low frequency supports a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) suggest that the Ala15Thr variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. In summary, additional data is needed to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
CardioboostCm	Uncertain	0.72
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.82	D
PhyloP100		8.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.65		Loss of MoRF binding (P = 0.1063);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.86
Mutation Taster		=40/60	disease causing

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: rs397516785; hg19: chr6-118880127;