chr15-63062263-G-A

Variant names:

• chr15-63062263-G-A
• rs199476317
• NM_001018005.2:c.688G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PP5_Very_Strong

The NM_001018005.2(TPM1):​c.688G>A​(p.Asp230Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000209327: Published functional studies demonstrate a damaging effect as this variant significantly impairs sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.88
• Publications: 35 publications found

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000209327: Published functional studies demonstrate a damaging effect as this variant significantly impairs sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010; Memo et al., 2013); SCV000280541: "Lakdawala et al (2010) assessed the impact of the variant using an in vitro reconstituted sarcomere complex. They found inhibited sarcomere function with reduced calcium sensitivity, maximum activation and calcium affinity." PMID:20627712; SCV000060006: "In vitro studies supported that this variant impacts contractility (Lakdawala 2010)."; SCV000824509: Experimental studies have shown that this missense change affects TPM1 function (PMID: 23539503, 25242052, 25548289, 28600229, 28603979).; SCV005900541: Functional studies indicate this variant reduces calcium sensitivity and inhibits sarcomere function (PMID: 20117437, 23539503, 25241052, 25548289).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-63062263-G-A is Pathogenic according to our data. Variant chr15-63062263-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018005.2. 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
	TPM1	NM_001018005.2	MANE Select	c.688G>A	p.Asp230Asn	missense	Exon 7 of 10	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.814G>A	p.Asp272Asn	missense	Exon 8 of 10	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.814G>A	p.Asp272Asn	missense	Exon 8 of 11	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000403994.9	TSL:1 MANE Select	c.688G>A	p.Asp230Asn	missense	Exon 7 of 10	ENSP00000385107.4	P09493-1
	TPM1	ENST00000267996.11	TSL:1	c.688G>A	p.Asp230Asn	missense	Exon 7 of 9	ENSP00000267996.7	P09493-7
	TPM1	ENST00000288398.10	TSL:1	c.688G>A	p.Asp230Asn	missense	Exon 7 of 10	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (5)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y (1)
1	-	-	Primary dilated cardiomyopathy (1)
1	-	-	TPM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.074	T
Polyphen		0.91	P
Vest4		0.84
MutPred		0.60		Gain of MoRF binding (P = 0.0548)
MVP		0.92
MPC		2.5
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs199476317; hg19: chr15-63354462;