chr15-34793398-C-T

Variant names:

• chr15-34793398-C-T
• rs193922680
• NM_005159.5:c.301G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 18P and 4B. PS3 PM1 PP3_Strong PP5_Very_Strong BS2

The NM_005159.5(ACTC1):​c.301G>A​(p.Glu101Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005416396: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000207710: Published functional studies demonstrate a damaging effect resulting in a decrease in sarcomeric force generation (Bookwater et al., 2006; Monserrat et al., 2007; Chow et al., 2014); SCV000260669: Experimental studies have shown that this missense change affects ACTC1 function (PMID:16611632, 19799913, 21622575).; SCV000061995: "In vitro studies indicate that this variant leads to reduced affinity of myosin for actin and results in decreased force generation (Bookwalter 2006, Debold 2010, Chow 2014). Furthermore, a mouse model harboring this variant presented with hypertrophic cardiomyopathy and had a decreased lifespan (Song 2011)."; SCV005629072: "In the crystal structure of the actin monomer, this substitution is located on the surface of Sub-domain 1. The charge reversal caused by Glu101Lys substitution could destabilize the N-terminal domain of the ACTC1. Alternatively, the charge reversal could affect ACTC1 interactions with partner proteins."; SCV002754279: Functional studies have reported this mutation to result in slower motility, reduced average force, and a weakened interaction with cardiac myosin in the presence of ATP (Bookwalter CS et al. J. Biol. Chem., 2006 Jun;281:16777-84). In addition, transgenic mice expressing p.E101K were reported to have similar features of HCM as those seen in patients with this mutation (Song W et al. J. Biol. Chem., 2011 Aug;286:27582-93).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.91
• Publications: 36 publications found

Genes affected

ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005416396: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000207710: Published functional studies demonstrate a damaging effect resulting in a decrease in sarcomeric force generation (Bookwater et al., 2006; Monserrat et al., 2007; Chow et al., 2014); SCV000260669: Experimental studies have shown that this missense change affects ACTC1 function (PMID: 16611632, 19799913, 21622575).; SCV000061995: "In vitro studies indicate that this variant leads to reduced affinity of myosin for actin and results in decreased force generation (Bookwalter 2006, Debold 2010, Chow 2014). Furthermore, a mouse model harboring this variant presented with hypertrophic cardiomyopathy and had a decreased lifespan (Song 2011)."; SCV005629072: "In the crystal structure of the actin monomer, this substitution is located on the surface of Sub-domain 1. The charge reversal caused by Glu101Lys substitution could destabilize the N-terminal domain of the ACTC1. Alternatively, the charge reversal could affect ACTC1 interactions with partner proteins."; SCV002754279: Functional studies have reported this mutation to result in slower motility, reduced average force, and a weakened interaction with cardiac myosin in the presence of ATP (Bookwalter CS et al. J. Biol. Chem., 2006 Jun;281:16777-84). In addition, transgenic mice expressing p.E101K were reported to have similar features of HCM as those seen in patients with this mutation (Song W et al. J. Biol. Chem., 2011 Aug;286:27582-93).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_005159.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 15-34793398-C-T is Pathogenic according to our data. Variant chr15-34793398-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005159.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	NM_005159.5	MANE Select	c.301G>A	p.Glu101Lys	missense	Exon 3 of 7	NP_005150.1	P68032
	ACTC1	NM_001406482.1		c.301G>A	p.Glu101Lys	missense	Exon 2 of 6	NP_001393411.1	P68032
	ACTC1	NM_001406483.1		c.301G>A	p.Glu101Lys	missense	Exon 3 of 7	NP_001393412.1	P68032

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.301G>A	p.Glu101Lys	missense	Exon 3 of 7	ENSP00000290378.4	P68032
	ACTC1	ENST00000713613.1		c.412G>A	p.Glu138Lys	missense	Exon 4 of 8	ENSP00000518909.1	A0AAQ5BGG2
	ACTC1	ENST00000868408.1		c.301G>A	p.Glu101Lys	missense	Exon 3 of 7	ENSP00000538467.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
4	-	-	Hypertrophic cardiomyopathy 11 (4)
3	-	-	Dilated cardiomyopathy 1R (3)
2	-	-	Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Left ventricular noncompaction 4 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.036	D
Polyphen		0.79	P
Vest4		0.90
MutPred		0.94		Gain of methylation at E101 (P = 0.0049)
MVP		0.99
MPC		3.1
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.93
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs193922680; hg19: chr15-35085599; COSMIC: COSV51758448; COSMIC: COSV51758448;