rs1554967541

Positions:

• chr11-19186257-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003476.5(CSRP3):​c.373A>T​(p.Lys125Ter) variant causes a stop gained change. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP3 NM_003476.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.28

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-19186257-T-A is Pathogenic according to our data. Variant chr11-19186257-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 543042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.373A>T	p.Lys125Ter	stop_gained	4/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.204A>T	p.Ala68=	synonymous_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.373A>T	p.Lys125Ter	stop_gained	4/6	1	NM_003476.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 543042). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys125*) in the CSRP3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSRP3 are known to be pathogenic (PMID: 12642359, 14567970, 16352453, 20087448, 34558151). -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 18, 2017

Variant CSRP3 Lys125Ter c.373A>T in exon 5 of 7 (NM__003476.4, hg19 chr11-19207804-T-A) SCICD classification variant of uncertain significance We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: lack of case data for this variant and limited case data for truncating variants, unclear if heterozygous loss of function is a mechanism of disease in this gene. We have seen this variant in one person with HCM. Lab classification Case data summary:-Not reported in the literature. -Not listed in ClinVar. Predicted Consequence: - creates a premature translational stop signal - expected to result in an absent or disrupted protein product - unclear whether loss-of-function variants in CSRP3 cause disease See below for details. Population Data: ExAC constraint metrics indicate that this gene may tolerate LoF (pLI 0.00); however per CardioDB, there is case excess of these types of variants (n is small) There is no variation at this codon in gnomAD. Metrics indicate adequate coverage. Two nearby residues have LoF variants in gnomAD (highest MAF: 0.013 in African Ancestry) Please see below for details. Predicted Consequence The Lys125Ter may cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, most disease-causing variants in the CSRP3 gene are missense changes (Stenson P et al., 2014). Vafiadaki et al, 2014 reported an alternate CSRP3 transcript lacking exons 3 and 4 which results in a frameshift of the remaining 22 amino acids. Case Data for Truncation Variants A few truncating variants have been observed in patients with hypertrophic cardiomyopathy but there is very limited segregation evidence. Different, Nearby Truncation Variant Population data: Arg122Ter Highest MAF in African ancestry population: 0.013%. The Arg122Ter was reported online in 3 of 123.057 total individuals (MAF: 0.001%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, and Latino descent. Specifically, the variant was observed in: 2 of 7,651 individuals of African descent (MAF=0.013%) 1 of 15,391 individuals of Ashkenazi Jewish descent (MAF=0.003%) The phenotype of those individuals is not publicly available. The dataset is composed of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.76
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554967541; hg19: chr11-19207804;