rs145300736

Positions:

• chr11-19188269-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_003476.5(CSRP3):​c.148G>A​(p.Ala50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,612,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A50E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_003476.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-19188268-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.148G>A	p.Ala50Thr	missense_variant	3/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.113-1921G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.148G>A	p.Ala50Thr	missense_variant	3/6	1	NM_003476.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 250998 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135652

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1460532 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 726574

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000444 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 50 of the CSRP3 protein (p.Ala50Thr). This variant is present in population databases (rs145300736, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20474083, 27532257). ClinVar contains an entry for this variant (Variation ID: 44687). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2011

Variant classified as Uncertain Significance - Favor Benign. The Ala50Thr varian t has not been identified in 1 individual with DCM out of >350 Caucasian individ uals tested and was absent from 344 Caucasian and 376 Black control chromosomes tested by our laboratory (Zimmerman 2010). Alanine (Ala) at position 50 is highl y conserved across evolutionarily distant species, suggesting that a change may negatively impact the protein's function, though fruitfly carries a threonine (t he same amino acid as this variant) and C. elegans carries a cystine. While cons ervation and absence in controls support a pathogenic role of the Ala50Thr varia nt, it was absent in an affected family member, which raises the possibility tha t it is benign. In summary, additional data is needed to clarify the clinical s ignificance of this variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 08, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2021

The c.148G>A (p.A50T) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the alanine (A) at amino acid position 50 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;T
Eigen	Benign	0.063
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.3	L;.;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.060	N;.;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.34	T;.;.;T
Sift4G	Benign	0.19	T;.;.;T
Polyphen		0.58	P;.;P;P
Vest4		0.83
MVP		0.90
MPC		0.070
ClinPred		0.094	T
GERP RS		5.6
Varity_R		0.23
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145300736; hg19: chr11-19209816; COSMIC: COSV56390503;