NM_033337.3:c.80G>C

Variant names:

• chr3-8733956-G-C
• rs116840778
• NM_033337.3:c.80G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_033337.3(CAV3):​c.80G>C​(p.Arg27Pro) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 6.40
• Publications: 17 publications found

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]

SSUH2 (HGNC:24809): (ssu-2 homolog) Involved in odontogenesis. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SSUH2 Gene-Disease associations (from GenCC):

• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_033337.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-8733956-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.83011 (below the threshold of 3.09). Trascript score misZ: 0.9876 (below the threshold of 3.09). GenCC associations: The gene is linked to rippling muscle disease 2, hypertrophic cardiomyopathy 1, long QT syndrome 9, distal myopathy, Tateyama type, inherited rippling muscle disease, Brugada syndrome, autosomal dominant limb-girdle muscular dystrophy type 1C, caveolinopathy, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-8733956-G-C is Pathogenic according to our data. Variant chr3-8733956-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31747.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	NM_033337.3	MANE Select	c.80G>C	p.Arg27Pro	missense	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.80G>C	p.Arg27Pro	missense	Exon 1 of 3	NP_001225.1	P56539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	ENST00000343849.3	TSL:1 MANE Select	c.80G>C	p.Arg27Pro	missense	Exon 1 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.80G>C	p.Arg27Pro	missense	Exon 1 of 3	ENSP00000380525.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8503C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	CAV3-related disorder (1)
1	-	-	Long QT syndrome (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Loss of stability (P = 0.0538)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.025	Neutral
Varity_R		0.95
gMVP		0.98
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs116840778; hg19: chr3-8775642;