rs112626848

chr3-8745655-G-Achr3-8745655-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_033337.3(CAV3):c.244G>A(p.Val82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V82A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 3.43

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]

OXTR (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_033337.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.2919835).
• BS2: High AC in GnomAd at 9 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.244G>A	p.Val82Ile	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.244G>A	p.Val82Ile	missense_variant	2/3
OXTR	XR_007095681.1	n.1885-3053C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.244G>A	p.Val82Ile	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.244G>A	p.Val82Ile	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11665G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000956 AC: 24 AN: 250942 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135662

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727174

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000883 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 16, 2016	p.Val82Ile (c.244G>A) in exon 2 of the CAV3 gene (NM_033337.2) We have seen this variant in a person with HCM who also had a very likely pathogenic MYBPC3 variant. Testing was performed by Invitae. Given the lack of gene level evidence associating the CAV3 gene with hypertrophic cardiomyopathy and case data linking the variant to LongQT syndrome that is somewhat undercut by population frequency, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene level evidence for CAV3 Both knockout and transgenic mouse models of CAV3 show evidence of HCM with progressive diastolic dysfunction (Aravamudan et al, 2003; Ohsawa et al, 2004). Despite this, human data points towards CAV3 variants causing skeletal muscle disease, not cardiomyopathy. Hayashi et al (2004) reported two siblings with HCM and p.T63S in CAV3. The variant was not inherited from their mother, so it was assumed to have come from their affected father, who was unavailable for study. Variant level evidence for CAV3 Val82Ile The Val82Ile variant has been seen in at least 3 unrelated cases of Long QT syndrome (not including this patient's family). It has not been reported in association with cardiomyopathy. Lariccia et al., 2014 reported it in a person with adult-onset sudden cardiac death. Lieve et al., 2013 reported the variant in a person with Long QT who also had a varian in KCNH2. The Invitae report notes that, "The valine residue is moderately conserved and there is a small physicochemical difference between valine and Isoleucine. An abstract from the 35th congresso nazionale Della Soicieta Italiana di Farmacologia reported it in an Italian patient with Long QT (http://congresso.sifweb.org/archivio/cong35/congresso_abs_view.php?id=244). Lariccia et al., 2014 reported that the variant caused increased protein expression, reduced targeting to the plasma membrane and impaired extracellular signal regulated kinase activation. The variant was reported online in 7 of 60,401 individuals (MAF: 0.0058%) in the Exome Aggregation Consortium Dataset (EXAC; http://exac.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino descent. Specifically, the variant was observed in 3 of 33,239 individuals of non-Finnish European descent (0.005% MAF), 1 of 5,189 people of African descent (MAF: 0.0096%), 1 of 5752 people of Latino descent (MAF 0.0087%), 1 of 8,210 people of South Asian descent (MAF: 0.006%, and 1 of 449 people of Other descent (MAF: 0.001%) . The phenotype of those individuals is not publicly available. The dataset is comprised 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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24917393, 23631430, 31737537, 30847666) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jun 24, 2022

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 22, 2016

- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

May 19, 2020

ACMG classification criteria: PS3, PS4, PP2 -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 82 of the CAV3 protein (p.Val82Ile). This variant is present in population databases (rs112626848, gnomAD 0.03%). This missense change has been observed in individual(s) with various cardiac conditions (PMID: 23631430, 24917393, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 279733). 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. Experimental studies have shown that this missense change affects CAV3 function (PMID: 24917393). 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

Jul 27, 2022

The p.V82I variant (also known as c.244G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 244. The valine at codon 82 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in association with long QT syndrome and sudden cardiac death (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This alteration was also noted to have a cell expression profile that was altered from the wildtype (Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This amino acid position is not well conserved in available vertebrate species. 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	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	21
Dann	Benign	0.64
DEOGEN2	Uncertain	0.51	D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.75	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-1.3	N;N
MutationTaster	Benign	0.54	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0080	B;B
Vest4		0.35
MVP		0.47
MPC		0.43
ClinPred		0.025	T
GERP RS		2.8
Varity_R		0.042
gMVP		0.51

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

Other links and lift over

dbSNP: rs112626848; hg19: chr3-8787341; COSMIC: COSV57479298; COSMIC: COSV57479298;