rs397516857

Variant names:

• chr11-19192402-G-A
• rs397516857
• NM_003476.5:c.47C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-19192402-G-A
• chr11-19192402-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_003476.5(CSRP3):​c.47C>T​(p.Thr16Ile) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.08
• Publications: 0 publications found

Genes affected

CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

CSRP3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD, SD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• hypertrophic cardiomyopathy 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1M

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-19192403-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 585275.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.47C>T	p.Thr16Ile	missense_variant	Exon 2 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.47C>T	p.Thr16Ile	missense_variant	Exon 2 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.47C>T	p.Thr16Ile	missense_variant	Exon 2 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2010

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. Variants in the CSRP3 gene have been identified in patients with HCM as well as DCM. However, t he Thr16Ile variant has not been reported in the literature. Threonine (Thr) at position 16 is conserved across several species (including mammals, amphibians, and birds); however, fly and worm, carry a different amino acid (serine) at this position, slightly reducing the likelihood that the change detected in this ind ividual may be pathogenic. On the other hand, the variant is present in two affe cted individuals in this family, which is consistent (but does not prove) a path ogenic role. In summary, in the absence of additional data (such as family stud ies, healthy control data or functional studies) the significance of this varian t cannot be determined. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;.;D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D;.;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.1	M;.;.;M;M;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D;.;.;.;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;.;.;.;D;.
Sift4G	Uncertain	0.0040	D;.;.;.;D;.
Polyphen		0.96	D;.;.;D;D;.
Vest4		0.81
MutPred		0.59		Gain of methylation at K15 (P = 0.0575);Gain of methylation at K15 (P = 0.0575);Gain of methylation at K15 (P = 0.0575);Gain of methylation at K15 (P = 0.0575);Gain of methylation at K15 (P = 0.0575);Gain of methylation at K15 (P = 0.0575);
MVP		0.97
MPC		0.28
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.67
gMVP		0.41
Mutation Taster		=41/59	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: rs397516857; hg19: chr11-19213949;