rs397516784

Variant names:

• chr6-118558956-TAAG-T
• rs397516784
• NM_002667.5:c.40_42delAGA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM4_SupportingPP5_Strong

The NM_002667.5(PLN):c.40_42delAGA (p.Arg14del) variant causes a conservative inframe deletion change. The variant results in an in-frame change. The variant allele was found at a cumulative frequency of 0.0000062 (AC=10) in the gnomAD database across 1,613,470 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.28). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000061240: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012 a, Ceholski 2012b, Haghighi 2012)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PLN NM_002667.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1
• Conservation: PhyloP100: 8.28
• Publications: 198 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]

PLN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1P

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• hypertrophic cardiomyopathy 18

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000061240: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012 a, Ceholski 2012b, Haghighi 2012).; SCV000236300: An in vitro functional study reported that R14del is a partial inhibitor of the sarcoplasmic reticulum calcium pump, and that it inhibits the phospholamban-protein kinase A interaction (Ceholski et al., 2012).; SCV000280420: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012a, Ceholski 2012b, Haghighi 2012).; SCV003802801: "In-vitro cell culture-based functional studies have shown that this variant results in the inhibition of SERCA, which is an important ATP-dependent calcium pump in the sarcoplasmic reticulum, and in-vivo studies have shown that transgenic mice that express this variant in the heart recapitulate the human cardiac phenotype." PMID:16432188; PMID:22155237; PMID:22427649; SCV000287496: Experimental studies have shown that this variant affects PLN function (PMID: 16432188, 22155237, 22707725).; SCV002557137: Functional analysis has shown that this variant has a dominant negative effect and results in sarcoplasmic reticulum Ca2+-ATPase inhibition. Additionally, transgenic mice develop DCM, abnormal histopathology and suffer premature death (PMID: 16432188).; SCV000318486: Functional assays have demonstrated that this alteration disrupts protein function and leads to dominant negative effects (Haghighi K et al. Proc Natl Acad Sci. U.S.A. 2006;103(5):1388-93; Haghighi K et al. J Mol Cell Cardiol. 2012;52(3):773-82; Ceholski D et al. J Biol Chem. 2012;287(32):26596-605; Ceholski DK et al. J Biol Chem. 2012;287(20):16521-9).; SCV006076320: Multiple functional studies, including mouse models, have demonstrated that the p.Arg14del variant has a deleterious impact on protein function (PMID:22707725; PMID:22155237; PMID:27450564).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 5 pathogenic, 1 benign rare missense variants (OR vs. background: 18.3).; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PM4Protein length change in non-repeat region		Single amino-acid in-frame indel in non-repetitive region — protein length change, supporting (PM4 +1); In-frame indel in non-repetitive region — protein length change (1 AA).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (21/22 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002667.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLN	NM_002667.5	MANE Select	c.40_42delAGA	p.Arg14del	conservative_inframe_deletion	Exon 2 of 2	NP_002658.1	Q5R352
	CEP85L	NM_001042475.3	MANE Select	c.1020+6570_1020+6572delCTT		intron	N/A	NP_001035940.1	Q5SZL2-1
	CEP85L	NM_001178035.2		c.1029+6570_1029+6572delCTT		intron	N/A	NP_001171506.1	Q5SZL2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.40_42delAGA	p.Arg14del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000350132.5	P26678
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6570_1020+6572delCTT		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6570_1029+6572delCTT		intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251122	Cov:
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461292	Cov:
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000445	AC:1	Hom:0	AN:22458	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00	0	113152	0.0000105	2	190650

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Dilated cardiomyopathy 1P (6)
2	-	-	Cardiomyopathy (2)
1	1	-	Primary dilated cardiomyopathy (2)
1	-	-	Arrhythmogenic right ventricular dysplasia 9 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 18 (1)
1	-	-	PLN-related cardiomyopathy (1)
1	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	42/58	disease causing (ClinVar)
PhyloP100	Pathogenic	8.3

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397516784;

hg19: chr6-118880119;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar