11-19188227-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003476.5(CSRP3):c.190C>A(p.Arg64Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R64C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.190C>A	p.Arg64Ser	missense_variant	3/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.113-1879C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.190C>A	p.Arg64Ser	missense_variant	3/6	1	NM_003476.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251244 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135786

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461290 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 64 of the CSRP3 protein (p.Arg64Ser). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2022

The p.R64S variant (also known as c.190C>A), located in coding exon 2 of the CSRP3 gene, results from a C to A substitution at nucleotide position 190. The arginine at codon 64 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;D;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.5	L;.;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D;.;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.010	D;.;.;D
Polyphen		0.75	P;.;P;P
Vest4		0.63
MutPred		0.58		Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);
MVP		0.96
MPC		0.14
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.73
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368392588; hg19: chr11-19209774;