3-8745671-T-C

Position:

chr3-8745671-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1PP3_StrongBS1_SupportingBS2

The NM_033337.3(CAV3):c.260T>C(p.Leu87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,082 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3O:1

Conservation

PhyloP100: 7.61

Variant links:

Genes affected

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

CAV3 links:

OXTR (HGNC:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

OXTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a intramembrane_region Helical (size 20) in uniprot entity CAV3_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_033337.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000369 (54/1461864) while in subpopulation NFE AF= 0.0000405 (45/1112000). AF 95% confidence interval is 0.0000308. There are 0 homozygotes in gnomad4_exome. There are 20 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 54 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV3	NM_033337.3 link	c.260T>C	p.Leu87Pro	missense_variant	2/2	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 link	c.260T>C	p.Leu87Pro	missense_variant	2/3		NP_001225.1	P56539
OXTR	XR_007095681.1 link	n.1885-3069A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAV3	ENST00000343849.3 link	c.260T>C	p.Leu87Pro	missense_variant	2/2	1	NM_033337.3	ENSP00000341940.2	P56539
CAV3	ENST00000397368.2 link	c.260T>C	p.Leu87Pro	missense_variant	2/3	1		ENSP00000380525.2	P56539
CAV3	ENST00000472766.1 link	n.155+11681T>C		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251160

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135798

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727230

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000549

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rippling muscle disease 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

SUDDEN INFANT DEATH SYNDROME

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 87 of the CAV3 protein (p.Leu87Pro). This variant is present in population databases (rs28936685, gnomAD 0.002%). This missense change has been observed in individual(s) with rippling muscle disease and/or sudden unexpected death (PMID: 12666119, 35027292). This variant is also known as L86P. ClinVar contains an entry for this variant (Variation ID: 8284). 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 disruptive. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2020

The c.260T>C (p.L87P) alteration is located in exon 2 (coding exon 2) of the CAV3 gene. This alteration results from a T to C substitution at nucleotide position 260, causing the leucine (L) at amino acid position 87 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (CAV3)

Apr 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

.;T

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.031

D;D

Polyphen

0.99

D;D

Vest4

0.78

MVP

1.0

MPC

1.7

ClinPred

0.98

GERP RS

4.6

Varity_R

0.98

gMVP

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over